NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites
Open accessAbstract
ATR and ATM kinases are central to the checkpoint activation in response to DNA damage and replication stress. However, the nature of the signal, which initially activates these kinases in response to UV damage, is unclear. Here, we have shown that DDB2 and XPC, two early UV damage recognition factors, are required for the damage-specific ATR and ATM recruitment and phosphorylation. ATR and ATM physically interacted with XPC and promptly localized to the UV damage sites. ATR and ATM recruitment and their phosphorylation were negatively affected in cells defective in DDB2 or XPC functions. Consequently, the phosphorylation of ATR and ATM substrates, Chk1, Chk2, H2AX, and BRCA1 was significantly reduced or abrogated in mutant cells. Furthermore, UV exposure of cells defective in DDB2 or XPC resulted in a marked decrease in BRCA1 and Rad51 recruitment to the damage site. Conversely, ATR- and ATM-deficiency failed to affect the recruitment of DDB2 and XPC to the damage site, and therefore did not influence the NER efficiency. These findings demonstrate a novel function of DDB2 and XPC in maintaining a vital cross-talk with checkpoint proteins, and thereby coordinating subsequent repair and checkpoint activation.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
0 of 72 cited sources checked · 0 supported · 0 flagged
- Findingown data
Neither DDB2 nor XPC localization to damage sites is affected in ATR- or ATM-compromised cells.
“The data showed that neither the DDB2 nor the XPC localization to the damage sites was impacted in ATR- or ATM-compromised cells (Fig. 3C).”
Quote in the paperSubstantial claim - Findingown data
Quantitative analysis showed a significant reduction in localized BRCA1 and Rad51 foci in both XP-E and XP-C cells compared with NHF cells.
“Quantitative analysis revealed a significant reduction in the localized foci of BRCA1 and Rad51 in both XP-E and XP-C cells as compared to NHF cells (Fig. 5B), indicating that DDB2 and XPC are required for optimal levels of recruitment of BRCA1 and Rad51.”
Quote in the paperSubstantial claim - Findingown data
NHF cells depleted of DDB2 and XPC also have lower levels of ATR, ATM, and H2AX phosphorylation.
“Our data showed that NHF cells depleted of DDB2 and XPC proteins also had lower levels of ATR, ATM, and H2AX phosphorylation (Fig. 4B).”
Quote in the paperSubstantial claim - Findingown data
Knockdown of ATR does not significantly alter NER efficiency, measured by removal of CPD and 6-4PP lesions, in normal and ATR-compromised cells.
“Upon ATR knockdown, the efficiency of NER did not change significantly as assessed by the extent of CPD and 6-4PP removal in normal and ATR-compromised cells (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
UV exposure of cells defective in DDB2 or XPC causes a marked decrease in BRCA1 and Rad51 recruitment to damage sites.
“Furthermore, UV exposure of cells defective in DDB2 or XPC resulted in a marked decrease in BRCA1 and Rad51 recruitment to the damage site.”
Quote in the paperSubstantial claim
- Findingown data
ATR and ATM localize to UV damage sites.
“Here we have further confirmed the specific ATR and ATM localization to the UV damage sites via micropore immunofluorescence (Fig.1 A).”
Quote in the paperSubstantial claim - Findingown data
In ATR-deficient cells, 39% of CPD lesions remained after 24 h, compared with 37% in ATR-proficient cells.
“CPD remaining after 24 h in ATR-deficient cells was 39% compared to 37% in ATR-proficient cells (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
In ATR-deficient cells, 15% of 6-4PP lesions remained after 8 h, compared with 22% in ATR-proficient cells.
“6-4PP remaining after 8 h in ATR-deficient cells was 15% compared to 22% in ATR-proficient cells (Fig. 6B).”
Quote in the paperSubstantial claim - Findingown data
The p21 level decreased significantly in NHF, XP-E, and XP-C cells.
“Interestingly, we observed the p21 level decreased significantly in NHF, XP-E and XP-C cells.”
Quote in the paperNot a substantial claim - Findingown data
The rate of removal of CPD and 6-4PP lesions does not differ significantly between ATM-deficient and ATM-proficient cells.
“Similarly, the rate of CPD and 6-4PP removal did not show a significant difference in ATM-deficient cells compared to ATM-proficient cells (Fig. 6A).”
Quote in the paperSubstantial claim - Findingown data
The decrease in ATR/ATM foci coincided with reduced H2AX phosphorylation in XP-E and XP-C cells.
“The decrease was coincident with the reduced H2AX phosphorylation seen in parallel in XP-E and XP-C cells.”
Quote in the paperSubstantial claim - Findingown data
XPC appears distinctly and robustly at DNA damage sites in ATR-defective Seckel and ATM-deficient AT cells.
“This conclusion was further reaffirmed by the distinct and robust appearance of XPC at the DNA damage sites in ATR-defective Seckel and ATM-deficient AT cells (Fig. 3E).”
Quote in the paperSubstantial claim - Findingown data
Cells defective in XPC or DDB2 function show a large reduction in phosphorylation of ATR, ATM, and their substrate proteins.
“Moreover, cells defective in XPC or DDB2 function exhibit a great reduction in the phosphorylation of ATR, ATM, and their substrate proteins (Fig. 2C, Fig. 4A, B)”
Quote in the paperSubstantial claim - Findingown data
ATR and ATM associate with XPC in response to UV irradiation.
“Our results show that ATR and ATM associate with XPC in response to UV irradiation.”
Quote in the paperSubstantial claim - Findingown data
ATR phosphorylation at S428 and ATM phosphorylation at S1981 are markedly reduced or completely abrogated in XP-E and XP-C cells compared with NHF cells.
“Using the available antibodies, we observed that the ATR phosphorylation at S428 and ATM phosphorylation at S1981 were markedly reduced or completely abrogated in XP-E and XP-C cells as compared to the vivid phosphorylation in NHF cells (Fig. 2C).”
Quote in the paperSubstantial claim - Findingown data
No significant difference in intensity was seen with a high 100 J/m2 radiation dose.
“Notably, we did not see a significant difference in the intensity using a high (100 J/m2) dose of radiation.”
Quote in the paperNot a substantial claim - Findingown data
XPC physically interacts with ATR and ATM only after UV damage.
“ATR and ATM physically interacted with XPC and promptly localized to the UV damage sites.”
- Also stated in: § 1. Introduction · plain
“Here, we show that XPC physically interacts with ATR and ATM.”
- Also stated in: § 3.1 ATR and ATM localize to the UV damage site and interact with XPC · plain
“We observed that both ATR and ATM physically interacted with XPC only in response to UV damage (Fig. 1D).”
Quote in the paperSubstantial claim - Also stated in: § 1. Introduction · plain
- Findingown data
About 30-35% of cells showed DDB2 and XPC foci in control siRNA-, ATR siRNA-, or ATM shRNA-treated cells.
“For instance, the estimation of damage co-localized foci indicated that about 30-35% cells showed DDB2 and XPC foci in control siRNA-, ATR siRNA-, or ATM shRNA-treated cells (Fig. 3D).”
Quote in the paperSubstantial claim - Findingown data
In ATM-deficient cells, 17% of 6-4PP lesions remained after 8 h, compared with 29% in ATM-proficient cells.
“The extent of 6-4PP removal at 8 h was 17% in ATM-deficient cells as compared to 29% in ATM-proficient cells.”
Quote in the paperSubstantial claim - Findingown data
p53 was promptly induced and continued to increase up to 8 hours after irradiation in NHF, XP-E, and XP-C cells.
“As shown in Fig. 4C, p53 was promptly induced and continued to increase up to 8 hr post-irradiation in all three cell lines, indicating that p53-dependent checkpoint pathway is not influenced by the absence of DDB2 or XPC.”
Quote in the paperSubstantial claim - Findingown data
p53 upregulation is not affected in cells defective in DDB2 and XPC function.
“On the other hand, we found that p53 upregulation is not affected in the cells defective in DDB2 and XPC function (Fig. 4C).”
Quote in the paperSubstantial claim - Findingown data
Phospho-BRCA1 and Rad51 show lower intensities and diffused foci in XP-E and XP-C cells compared with NHF cells.
“As expected, we noticed that phospho-BRCA1 and Rad51 exhibited lower intensities and diffused foci in XP-E and XP-C cells as compared to the pronounced foci of NHF cells.”
Quote in the paperSubstantial claim - Findingown data
In ATM-deficient cells, 19% of CPD lesions remained after 24 h, compared with 28% in ATM-proficient cells.
“The extent of CPD removal at 24 h was 19% in ATM-deficient cells as compared to 28% in ATM-proficient cells (Fig. 6C).”
Quote in the paperSubstantial claim - Findingown data
The defect in BRCA1 phosphorylation was more prominent in XP-C cells than in XP-E cells.
“Interestingly, we found that the defect in the BRCA1 phosphorylation in XP-C cells was more prominent than in XP-E cells (Fig. 4A).”
Quote in the paperNot a substantial claim - Findingown data
DDB2 and XPC affect phosphorylation of both Chk1 and Chk2 in response to UV damage.
“Our results showed that DDB2 and XPC affect both Chk1 and Chk2 phosphorylation in response to UV damage (Fig. 4A)”
Quote in the paperSubstantial claim - Findingown data
UV damage-specific ATM foci were reduced from 35% in control shRNA-treated cells to only 2% in ATM shRNA-treated cells.
“Similarly, UV damage specific ATM foci were reduced from 35% in control shRNA-treated cells to only 2% in ATM shRNA-treated cells.”
Quote in the paperNot a substantial claim - Findingown data
ATR and ATM localization is dramatically reduced in NER-defective XP-E and XP-C cells compared with NHF cells.
“Quantitative estimates of different foci formation revealed that ATR and ATM localization was dramatically affected in NER-defective XP-E and XP-C cells as compared to NHF cells (Fig. 2A).”
Quote in the paperSubstantial claim - Findingown data
H2AX and BRCA1 phosphorylations are negatively affected in XP-E and XP-C cells.
“Our results showed that H2AX and BRCA1 phosphorylations were negatively affected in XP-E and XP-C cells (Fig. 5A).”
Quote in the paperSubstantial claim - Findingown data
Phosphorylated Chk1 (Ser296), Chk2 (Thr68), BRCA1 (S1524), and γ-H2AX (Ser139) are dramatically reduced or completely abrogated in cells lacking functional DDB2 and XPC.
“As expected, the levels of phosphorylated forms of target proteins Chk1 (Ser 296), Chk2 (Thr68), BRCA1 (S1524), and γ-H2AX (Ser139) were either dramatically reduced or completely abrogated in the absence of functional DDB2 and XPC (Fig. 4A), indicating a defect in the ATR and ATM signaling pathways.”
Quote in the paperSubstantial claim - Findingown data
Optimal recruitment of BRCA1 and Rad51 to sites of UV damage depends on DDB2 and XPC.
“DDB2 and XPC are required for optimal levels of recruitment of BRCA1 and Rad51.”
- Also stated in: § 4.3. DDB2 and XPC promote DNA repair through BRCA1-and Rad51-dependent pathway · boosted
“Indeed, we showed that DDB2 and XPC clearly play a role in the recruitment of BRCA1 and Rad51 proteins to the UV damage site (Fig. 5).”
Quote in the paperSubstantial claim - Also stated in: § 4.3. DDB2 and XPC promote DNA repair through BRCA1-and Rad51-dependent pathway · boosted
- Findingown data
ATR and ATM do not facilitate recruitment of DDB2 and XPC to UV damage sites.
“We also revealed that ATR and ATM do not facilitate recruitment of DDB2 and XPC to the UV damage site, and consequently fail to influence NER efficiency.”
Quote in the paperSubstantial claim - Premisecitation
In yeast, UV-induced DNA damage causes checkpoint activation without NER lesion processing.
“In yeast, UV-induced DNA damage results in checkpoint activation independent of NER lesion processing [33, 34].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [33] Giannattasio M Lazzaro F Longhese MP Plevani P Muzi-Falconi M Physical and functional interactions between nucleotide excision repair and DNA damage checkpoint EMBO J 23 2004 429 438 14726955 PMC1271758 source
Not checked in the free run.
- cites [34] Zhang H Taylor J Siede W Checkpoint arrest signaling in response to UV damage is independent of nucleotide excision repair in Saccharomyces cerevisiae J Biol Chem 278 2003 9382 9387 12522147 source
Not checked in the free run.
- Premisecitation
Recent studies, including the authors' own, suggest that ATM also participates in the NER pathway.
“Although DNA double strand breaks (DSB) primarily activates the ATM pathway, recent studies including ours have implicated a participatory role of ATM in the NER pathway [18, 19].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] Yajima H Lee KJ Zhang S Kobayashi J Chen BP DNA double-strand break formation upon UV-induced replication stress activates ATM and DNA-PKcs kinases J Mol Biol 385 2009 800 810 19071136 PMC2662442 source
Not checked in the free run.
- cites [19] Ray A Mir SN Wani G Zhao Q Battu A Zhu Q Wang QE Wani AA Human SNF5/INI1, a component of the human SWI/SNF chromatin remodeling complex, promotes nucleotide excision repair by influencing ATM recruitment and downstream H2AX phosphorylation Mol Cell Biol 29 2009 6206 6219 19805520 PMC2786693 source
Not checked in the free run.
- Interpretationown data
DDB2 and XPC regulate the ATR-Chk1 and ATM-Chk2 checkpoint signaling pathways.
“Collectively, these results show that DDB2 and XPC regulate ATR-Chk1 and ATM-Chk2 checkpoint signaling pathways.”
Quote in the paperSubstantial claim - Interpretationcitation
Checkpoint activation in XP-E or XP-C cells is intact.
“This is consistent with earlier studies showing that p21 degradation upon UV irradiation or low levels of p21 do not affect cell cycle checkpoint [57], and therefore we anticipate that checkpoint activation in XP-E or XP-C cells is intact.”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [57] Bendjennat M Boulaire J Jascur T Brickner H Barbier V Sarasin A Fotedar A Fotedar R UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promote DNA repair Cell 114 2003 599 610 13678583 source
Not checked in the free run.
- Interpretationcitation
The interaction between XPC and ATR/ATM appears to be a conserved response to various bulky DNA lesions.
“Thus, XPC and ATR/ATM interaction appears to be a conserved response to the induction of a variety of bulky lesions in the genome.”
Quote in the paperSubstantial claim - Interpretationreasoning
p53-dependent cell cycle arrest is not affected in cells defective in DDB2 and XPC function.
“As DNA damage triggers p53-dependent checkpoint arrest, we predict that p53-dependent cell cycle arrest is not affected in these cells.”
Quote in the paperSubstantial claim- Rests on an assumption: DNA damage triggers p53-dependent checkpoint arrest.
- Interpretationown data
DDB2 and XPC play a direct role in cell cycle checkpoint signaling.
“supporting a direct role of DDB2 and XPC in cell cycle checkpoint signaling.”
Quote in the paperSubstantial claim - Interpretationown data
Defective DDB2 and XPC function impairs the checkpoint signal transduction cascade after UV damage.
“Thus, defective DDB2 and XPC function caused an obvious impairment of checkpoint signal transduction cascade in response to UV damage.”
Quote in the paperSubstantial claim - Interpretationown data
DDB2 and XPC are needed for optimal recruitment of ATR and ATM to UV damage sites.
“These data indicated that DDB2 and XPC recognize the damaged lesion and are also needed for the optimal level of recruitment of ATR and ATM to the damage site.”
Quote in the paperSubstantial claim - Interpretationreasoning
DDB2/XPC act in DNA damage signaling through events similar to those used by Mre11-Rad50-Nbs1 or MSH2 to activate ATR/ATM.
“Apparently, DDB2/XPC act in DNA damage signaling through events similar to those provoked by the Mre11-Rad50-Nbs1 or MSH2 in activating ATR/ATM.”
Quote in the paperSubstantial claim - Interpretationown data
DDB2 and XPC are required for optimal recruitment of BRCA1 and Rad51.
“Quantitative analysis revealed a significant reduction in the localized foci of BRCA1 and Rad51 in both XP-E and XP-C cells as compared to NHF cells (Fig. 5B), indicating that DDB2 and XPC are required for optimal levels of recruitment of BRCA1 and Rad51.”
Quote in the paperSubstantial claim - Interpretationown data
DDB2 and XPC have a novel upstream role in regulating the recruitment and activation of ATR and ATM after UV irradiation of mammalian cells.
“Our study describes a novel upstream role of DDB2 and XPC in regulating ATR and ATM recruitment and activation following UV irradiation of mammalian cells.”
Quote in the paperSubstantial claim- The authors state this as an assumption: The DDB2/XPC complex represents the major sensor of UV damage.
- Interpretationreasoning
DDB2 and XPC participate in UV-induced damage signaling that leads to phosphorylation of BRCA1 and Rad51 downstream.
“This demonstrated that DDB2 and XPC are involved in UV-induced damage signaling which leads to downstream BRCA1 and Rad51 phosphorylation.”
Quote in the paperSubstantial claim - Interpretationreasoning
Formation of a fully functional DDB1-DDB2-XPC complex at the damage site is required for optimal recruitment of ATR and ATM.
“Therefore, we predict that fully functional DDB1-DDB2-XPC complex formation at the damage site is required for optimal recruitment of ATR and ATM.”
Quote in the paperSubstantial claim- Rests on an assumption: XPC-defective cells are impaired in the functional DDB-XPC complex.
- Interpretationown data
The p53-dependent checkpoint pathway is not influenced by the absence of DDB2 or XPC.
“As shown in Fig. 4C, p53 was promptly induced and continued to increase up to 8 hr post-irradiation in all three cell lines, indicating that p53-dependent checkpoint pathway is not influenced by the absence of DDB2 or XPC.”
Quote in the paperSubstantial claim - Interpretationown data
DDB2 and XPC recruitment to DNA damage sites is unaffected when ATR and ATM are absent.
“Thus, DDB2 and XPC recruitment to the DNA damage sites was unaffected in the absence of ATR and ATM.”
Quote in the paperSubstantial claim - Interpretationown data
DDB2 and XPC might have distinct effects on ATR-Chk1 and ATM-Chk2 signaling phosphorylations.
“Therefore, DDB2 and XPC might have distinct effects on phosphorylations of ATR-Chk1 and ATM-Chk2 signaling.”
Quote in the paperNot a substantial claim - Interpretationreasoning
DDB2 and XPC might influence the HR pathway after UV damage.
“All these findings indicate that DDB2 and XPC might influence the HR pathway after introduction of UV damage.”
Quote in the paperSubstantial claim - Interpretationreasoning
ATR and ATM are mainly involved in establishing checkpoint arrest and DNA repair through the HR-mediated pathway in response to UV damage.
“It seems that ATR and ATM are mainly involved in establishing checkpoint arrest and DNA repair through the HR-mediated pathway in response to UV damage.”
Quote in the paperSubstantial claim - Interpretationreasoning
Besides their canonical NER repair function, DDB2 and XPC play a definite role in regulating ATR-Chk1-BRCA1- and ATM-Chk2-BRCA1-dependent downstream signaling in the UV damage response.
“Thus, our observations are intriguing because we clearly show that, besides their canonical function as the core repair factors of NER, DDB2 and XPC also play a definite role in regulating ATR-Chk1-BRCA1- and ATM-Chk2-BRCA1-dependent downstream signaling in the realm of UV damage response.”
Quote in the paperSubstantial claim - Premisecitation
Single-strand breaks can also form upon processing of UV lesions.
“Furthermore, SSB can also form upon processing of UV-lesions [18, 19].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [18] Yajima H Lee KJ Zhang S Kobayashi J Chen BP DNA double-strand break formation upon UV-induced replication stress activates ATM and DNA-PKcs kinases J Mol Biol 385 2009 800 810 19071136 PMC2662442 source
Not checked in the free run.
- cites [19] Ray A Mir SN Wani G Zhao Q Battu A Zhu Q Wang QE Wani AA Human SNF5/INI1, a component of the human SWI/SNF chromatin remodeling complex, promotes nucleotide excision repair by influencing ATM recruitment and downstream H2AX phosphorylation Mol Cell Biol 29 2009 6206 6219 19805520 PMC2786693 source
Not checked in the free run.
- Interpretationreasoning
The interactions described in this work indicate a novel etiological link through dysregulated activation of two central kinases involved in tumorigenesis.
“The interactions described in this work herald a novel etiological link occurring through the dysregulated activation of two central kinases involved in tumorigenesis.”
Quote in the paperSubstantial claim
- The quote only partly states this claim. 2
- May combine two claims. 33
- Classified as probably not a substantial claim. 37
The quote only partly states this claim.
Findingown dataATR and ATM localize to damage sites in G1-arrested cells, independently of DNA replication.
“More importantly, we showed that ATR and ATM localize to damage sites in G1 arrested cells (Fig. 1C).”
- Also stated in: § 3.1 ATR and ATM localize to the UV damage site and interact with XPC · boosted
“This data further supports the involvement of ATR and ATM kinases in response to UV damage, which is clearly independent of DNA replication.”
Quote in the paperSubstantial claim- Also stated in: § 3.1 ATR and ATM localize to the UV damage site and interact with XPC · boosted
May combine two claims.
Findingown dataUV damage-specific ATR foci were present in about 35% of control siRNA-treated cells and only 5% of ATR siRNA-treated cells.
“Quantitative analysis showed that UV damage specific ATR foci were present in ~35% of control siRNA-treated cells, and only 5% of ATR siRNA-treated cells.”
Quote in the paperNot a substantial claimMay combine two claims.
Findingown dataKnockdown of ATR or ATM significantly reduces ATR or ATM foci in HeLa cells while XPC foci remain prominent.
“Both ATR and ATM exhibited distinct co-localization with XPC in control siRNA/shRNA-treated cells, but ATR or ATM foci were significantly diminished in cells respectively treated with ATR siRNA or ATM shRNA, even though the XPC foci were highly prominent in these cells (Fig. 3B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown data6-4PP co-localizes with pATM and γ-H2AX, showing that ATR/ATM signaling also responds to 6-4PP and is not specific to CPD.
“The 6-4PP also co-localized with pATM and γ-H2AX, demonstrating that the ATR/ATM signal transduction is also operating in response to 6-4PP, and not specific to CPD (Fig. 1B).”
Quote in the paperSubstantial claimMay combine two claims.
Findingown datap21 levels decreased in NHF, XP-E, and XP-C cells, with significant recovery by 8 hours in XP-C but not in NHF and XP-E cells.
“In contrast, p21 levels decreased in NHF cells as well as XP-E and XP-C with a significant recovery by 8 hr post-irradiation in XP-C but not in NHF and XP-E cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataXP-E and XP-C cells did not differ greatly in attenuated H2AX and phospho-Chk1 levels, but phospho-Chk2 levels were discernibly lower in XP-E than in XP-C cells.
“Interestingly, XP-E and XP-C cells did not exhibit a major difference in the attenuated levels of H2AX and phospho-Chk1, but the phospho-Chk2 levels were discernibly lower in XP-E as compared to XP-C cells.”
Quote in the paperSubstantial claimMay combine two claims.
Findingown dataDDB2 and XPC are needed for ATR and ATM recruitment to UV damage sites and for their phosphorylation.
“Here, we have shown that DDB2 and XPC, two early UV damage recognition factors, are required for the damage-specific ATR and ATM recruitment and phosphorylation.”
- Also stated in: § 1. Introduction · plain
“Both DDB2 and XPC facilitate ATR and ATM recruitment to the damage site, and promote their phosphorylation.”
- Also stated in: § 3.2. DDB2 and XPC facilitate ATR and ATM recruitment and phosphorylation · hedged
“These data indicated that DDB2 and XPC recognize the damaged lesion and are also needed for the optimal level of recruitment of ATR and ATM to the damage site.”
Quote in the paperSubstantial claim- Also stated in: § 1. Introduction · plain
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationATR- and ATM-mediated phosphorylation of BRCA1 and H2AX is needed for S and G2/M checkpoints and HR-mediated DNA repair during S and G2.
“Moreover, ATR- and ATM-mediated phosphorylation of BRCA1 and H2AX [22, 23] is required for S and G2/M phase checkpoints and homologous recombination (HR)-mediated DNA repair during S and G2 phases.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [22] Xie A Odate S Chandramouly G Scully R H2AX post-translational modifications in the ionizing radiation response and homologous recombination Cell Cycle 9 2010 3602 3610 20703100 PMC2980696 source
Not checked in the free run.
- cites [23] Chen J Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage Cancer Res 60 2000 5037 5039 11016625
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe DDB1-CUL4-ROC1 complex ubiquitylates XPC, which may increase XPC DNA binding and promote NER.
“The DDB1-CUL4-ROC1 complex ubiquitylates XPC, which may enhance DNA binding by XPC and promotes NER [6, 7].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [6] Sugasawa K Okuda Y Saijo M Nishi R Matsuda N Chu G Mori T Iwai S Tanaka K Tanaka K Hanaoka F UV-induced ubiquitylation of XPC protein mediated by UV-DDB-ubiquitin ligase complex Cell 121 2005 387 400 15882621 source
Not checked in the free run.
- cites [7] Li J Wang QE Zhu Q El-Mahdy MA Wani G Praetorius-Ibba M Wani AA DNA damage binding protein component DDB1 participates in nucleotide excision repair through DDB2 DNA-binding and cullin 4A ubiquitin ligase activity Cancer Res 66 2006 8590 8597 16951172 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationBRCA1, BRCA2, and Rad51 are needed for HR-mediated DNA repair and replication fork maintenance.
“Besides BRCA1, BRCA2, and Rad51 are also required for HR-mediated DNA repair and replication fork maintenance [25, 26].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [25] Lundin C Schultz N Arnaudeau C Mohindra A Hansen LT Helleday T RAD51 is involved in repair of damage associated with DNA replication in mammalian cells J Mol Biol 328 2003 521 535 12706714 source
Not checked in the free run.
- cites [26] Chen JJ Silver D Cantor S Livingston DM Scully R BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway Cancer Res 59 1999 1752s 1756s 10197592
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationATR is the main sensor of single-stranded DNA breaks caused by UV damage and replication stress.
“ATR is the primary sensor of single-stranded (ssDNA) breaks (SSB) caused by UV damage and replication stress.”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Cortez D Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling Genes Dev 19 2005 1007 1012 15879550 PMC1360198 source
Not checked in the free run.
- cites [16] Zou L Elledge SJ Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes Science 300 2003 1542 1548 12791985 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationNER can remove many structurally different lesions, including UV-induced CPD and 6-4PP.
“NER is a versatile DNA repair pathway that can remove a broad range of structurally unrelated lesions including UV-induced bulky DNA adducts cyclobutane pyrimidine dimers (CPD) and pyrimidine (6-4) pyrimidone photoproducts (6-4PP) [2].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [2] De Laat WL Jaspers NG Hoeijmakers JH Molecular mechanism of nucleotide excision repair Genes Dev 13 1999 768 785 10197977 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationJiang and Sancar showed that ATR binds damaged DNA directly without lesion processing.
“Jiang and Sancar showed direct binding of ATR to the damaged DNA without lesion processing, raising the possibility that ATR may activate the checkpoint signaling directly [30].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [30] Jiang G Sancar A Recruitment of DNA damage checkpoint proteins to damage in transcribed and nontranscribed sequences Mol Cell Biol 26 2006 39 49 16354678 PMC1317637 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationATR and ATM are the main checkpoint kinases turned on by DNA damage.
“The phosphoinositide-3-kinase-like kinases family of protein kinases including ATR (Ataxia telangiectasia- and Rad3- related) and ATM (Ataxia telangiectasia mutated) are the principal checkpoint kinases activated by DNA damage [13, 14].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [13] Sancar A Lindsey-Boltz LA Unsal-Kacmaz K Linn S Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints Annu Rev Biochem 73 2004 39 85 15189136 source
Not checked in the free run.
- cites [14] Shiloh Y ATM and ATR: networking cellular responses to DNA damage Curr Opin Genet Dev 119 2001 71 77 11163154 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDNA damage and replication intermediates increase DNA unwinding, leading to RPA-coated ssDNA accumulation that recruits ATR.
“It has been shown that DNA damage and replication intermediates increase the unwinding of DNA, leading to the accumulation of RPA-coated ss-DNA, which recruits ATR [15, 16].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Cortez D Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling Genes Dev 19 2005 1007 1012 15879550 PMC1360198 source
Not checked in the free run.
- cites [16] Zou L Elledge SJ Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes Science 300 2003 1542 1548 12791985 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationOh et al. reported that γH2AX foci form after UV irradiation in cells lacking NER.
“Recently, Oh et. al. reported γH2AX foci formation after UV-irradiation in cells lacking NER [32].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [32] Oh KS Bustin M Mazur SJ Appella E Kraemer KH UV-induced histone H2AX phosphorylation and DNA damage related proteins accumulate and persist in nucleotide excision repair-deficient XP-B cells DNA Repair (Amst) 10 2011 5 15 20947453 PMC3010519 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationATM phosphorylates Chk2, which triggers degradation of Cdc25A phosphatases and delays the cell cycle.
“ATM phosphorylates the checkpoint kinase Chk2, which also triggers degradation of Cdc25A phosphatases to delay the cell cycle [20].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [20] Bartek J Lukas J DNA damage checkpoints: from initiation to recovery or adaptation Curr Opin Cell Biol 19 2007 238 245 17303408 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationChk1 and Chk2 control functional associations among BRCA1, BRCA2, and Rad51 after DNA damage, promoting HR-mediated repair of stalled replication forks.
“Both Chk1 and Chk2 regulate the functional associations between BRCA1, BRCA2, and Rad51 proteins in response to DNA damage, and thus promote HR-mediated repair of stalled replication forks [27, 28].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [27] Sorensen CS Hansen LT Dziegielewski J Syljuasen RG Lundin C Bartek J Helleday T The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair Nat Cell Biol 7 2005 195 201 15665856 source
Not checked in the free run.
- cites [28] Falck J Mailand N Syljuasen RG Bartek J Lukas J The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis Nature 410 2001 842 847 11298456 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationXPA stabilizes the bubble and helps position XPF and XPG endonucleases for incisions that excise a 24-32 bp oligonucleotide containing the lesion.
“XPA stabilizes the bubble and aids in positioning the XPF and XPG endonucleases for respective 5’ and 3’ incisions to excise out a 24-32 bp oligonucleotide containing damaged lesion.”
Quote in the paperNot a substantial claim0 of 2 sources checkedClassified as probably not a substantial claim.
PremisecitationIn GG-NER, UV-DDB (DDB1 and DDB2) and XPC-RAD23B complexes recognize damage.
“In GG-NER, damage is recognized by the UV-DDB (DDB1 and DDB2) and XPC-RAD23B complexes [4, 5].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [4] Wakasugi M Kawashima A Morioka H Linn S Sancar A Mori T Nikaido O Matsunaga T DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair J Biol Chem 277 2002 1637 1640 11705987 source
Not checked in the free run.
- cites [5] Fitch ME Nakajima S Yasui A Ford JM In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product J Biol Chem 278 2003 46906 46910 12944386 source
Not checked in the free run.
May combine two claims.
PremisecitationThe DDB complex first recognizes CPD lesions and recruits XPC, whereas XPC can recognize 6-4PP lesions on its own.
“The DDB complex initially recognizes the CPD lesions and recruits XPC [4, 5, 8, 9], whereas XPC can independently recognize 6-4PP lesions [5].”
Quote in the paperNot a substantial claim0 of 4 sources checked- cites [4] Wakasugi M Kawashima A Morioka H Linn S Sancar A Mori T Nikaido O Matsunaga T DDB accumulates at DNA damage sites immediately after UV irradiation and directly stimulates nucleotide excision repair J Biol Chem 277 2002 1637 1640 11705987 source
Not checked in the free run.
- cites [5] Fitch ME Nakajima S Yasui A Ford JM In vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product J Biol Chem 278 2003 46906 46910 12944386 source
Not checked in the free run.
- cites [8] Sugasawa K Okamoto T Shimizu Y Masutani C Iwai S Hanaoka F A multistep damage recognition mechanism for global genomic nucleotide excision repair Genes Dev 15 2001 507 521 11238373 PMC312644 source
Not checked in the free run.
- cites [9] Luijsterburg MS Goedhart J Moser J Kool H Geverts B Houtsmuller AB Mullenders LH Vermeulen W van DR Dynamic in vivo interaction of DDB2 E3 ubiquitin ligase with UV-damaged DNA is independent of damage-recognition protein XPC J Cell Sci 120 2007 2706 2716 17635991 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationXPC helps recruit XPA, XPG, and TFIIH components that open the DNA helix around the damage to form a bubble.
“In turn, XPC helps in recruiting XPA, XPG, and TFIIH components that enable opening of the DNA helix around the damage site to form a bubble [8].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [8] Sugasawa K Okamoto T Shimizu Y Masutani C Iwai S Hanaoka F A multistep damage recognition mechanism for global genomic nucleotide excision repair Genes Dev 15 2001 507 521 11238373 PMC312644 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationActivated Chk1 phosphorylates Cdc25 phosphatases and inhibits them, delaying cell cycle progression.
“Activated Chk1 phosphorylates Cdc25 phosphatases to inhibit their function, and the cells delay progression through the cell cycle [17].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [17] Xiao Z Chen Z Gunasekera AH Sowin TJ Rosenberg SH Fesik S Zhang H Chk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents J Biol Chem 278 2003 21767 21773 12676925 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAfter DSBs, the MRN complex helps recruit ATM to damage sites and helps activate it by phosphorylation.
“In response to DSB, the lesion recognition factor Mre11-Rad50-Nbs1 (MRN) complex helps the recruitment of ATM to the damage site and its activation by phosphorylation [29].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [29] Lee JH Paull TT Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex Science 304 2004 93 96 15064416 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationVrouwe et al. reported that UV photolesions cause checkpoint activation through both NER-dependent and NER-independent routes.
“Furthermore, Vrouwe et al reported that UV-induced photolesions results in checkpoint activation in NER-dependent and -independent pathways [31].”
Quote in the paperSubstantial claim0 of 1 sources checked- cites [31] Vrouwe MG Pines A Overmeer RM Hanada K Mullenders LH UV-induced photolesions elicit ATR-kinase-dependent signaling in non-cycling cells through nucleotide excision repair-dependent and -independent pathways J Cell Sci 124 2011 435 446 21224401 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationGG-NER removes damage throughout the genome, while TC-NER preferentially removes damage in the transcribed strand of active genes.
“One sub-pathway of NER, global genome NER (GG-NER), removes damage from the entire genome, whereas DNA damage in the transcribed strand of active genes is preferentially eliminated by transcription-coupled NER (TC-NER) [3].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [3] Hanawalt PC Subpathways of nucleotide excision repair and their regulation Oncogene 21 2002 8949 8956 12483511 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationDefects in NER components cause XP, CS, and TTD, which are marked by UV sensitivity and a predisposition to skin cancers.
“Importantly, the defects in components of the NER pathway result in Xeroderma pigmentosum (XP), Cockayne syndrome (CS), and trichothiodystrophy which are characterized by sensitivity to UV irradiation and predisposition to skin cancers [11, 12].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [11] Reardon JT Sancar A Recognition and repair of the cyclobutane thymine dimer, a major cause of skin cancers, by the human excision nuclease Genes Dev 17 2003 2539 2551 14522951 PMC218148 source
Not checked in the free run.
- cites [12] De Boer J Hoeijmakers JH Nucleotide excision repair and human syndromes Carcinogenesis 21 2000 453 460 10688865 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisenone givenATR phosphorylates Chk1, causing checkpoint activation in G1, S, and G2/M phases.
“ATR phosphorylates Chk1, which results in checkpoint activation during G1, S, and G2/M phases.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationThe DNA damage response pathway is important for keeping the genome stable and preventing cancer.
“The DNA damage response (DDR) pathway plays a critical role in maintaining genomic stability and preventing carcinogenesis [1].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [1] Jackson SP Bartek J The DNA-damage response in human biology and disease Nature 461 2009 1071 1078 19847258 PMC2906700 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThese findings reveal a new function of DDB2 and XPC in cross-talk with checkpoint proteins, coordinating repair and checkpoint activation.
“These findings demonstrate a novel function of DDB2 and XPC in maintaining a vital cross-talk with checkpoint proteins, and thereby coordinating subsequent repair and checkpoint activation.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
InterpretationcitationThis supports the possibility that ATR and ATM are recruited after incision of UV damage.
“This supports the possibility of ATR and ATM recruitment after incision of the UV damage.”
Quote in the paperNot a substantial claimMay combine two claims.
Interpretationown dataATR and ATM are exclusively involved in checkpoint or DSB repair pathways through their effects on Chk1/Chk2 or BRCA1/Rad51, and they do not play an accessory role in NER.
“The results essentially support a model where ATR and ATM are exclusively involved in the checkpoint or DSB repair pathways through their influence on Chk1/Chk2 or BRCA1/Rad51 proteins, but do not play an accessory role in the NER pathway.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataATR and ATM deficiency does not affect DDB2 and XPC recruitment to damage sites and therefore does not influence NER efficiency.
“Conversely, ATR- and ATM-deficiency failed to affect the recruitment of DDB2 and XPC to the damage site, and therefore did not influence the NER efficiency.”
Quote in the paperSubstantial claimMay combine two claims.
Interpretationown dataDDB2 and XPC are required for efficient Chk1-Chk2-mediated checkpoint arrest, but not for p53-mediated checkpoint arrest.
“These observations suggest that DDB2 and XPC are required for efficient Chk1-Chk2-mediated checkpoint arrest, but not p53-mediated checkpoint arrest.”
Quote in the paperSubstantial claim- Rests on an assumption: Chk1 and Chk2 phosphorylation is required for cell cycle arrest by triggering Cdc25A degradation.
Classified as probably not a substantial claim.
PremisecitationSeveral studies have reported that NER factor-mediated lesion processing might be required for γH2AX foci formation.
“However, several studies reported that lesion processing by NER factors might be an essential step in γH2AX foci formation [35-39].”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [35] Matsumoto M Yaginuma K Igarashi A Imura M Hasegawa M Iwabuchi K Date T Mori T Ishizaki K Yamashita K Inobe M Matsunaga T Perturbed gap-filling synthesis in nucleotide excision repair causes histone H2AX phosphorylation in human quiescent cells J Cell Sci 120 2007 1104 1112 17327276 source
Not checked in the free run.
- cites [36] Marti TM Hefner E Feeney L Natale V Cleaver JE H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks Proc Natl Acad Sci U S A 103 2006 9891 9896 16788066 PMC1502549 source
Not checked in the free run.
- cites [37] Hanasoge S Ljungman M H2AX phosphorylation after UV irradiation is triggered by DNA repair intermediates and is mediated by the ATR kinase Carcinogenesis 28 2007 2298 2304 17615256 source
Not checked in the free run.
- cites [38] Marini F Nardo T Giannattasio M Minuzzo M Stefanini M Plevani P Muzi FM DNA nucleotide excision repair-dependent signaling to checkpoint activation Proc Natl Acad Sci U S A 103 2000 17325 17330 17088560 PMC1859929 source
Not checked in the free run.
- cites [39] Sertic S Pizzi S Cloney R Lehmann AR Marini F Plevani P Muzi-Falconi M Human exonuclease 1 connects nucleotide excision repair (NER) processing with checkpoint activation in response to UV irradiation Proc Natl Acad Sci U S A 108 2011 13647 13652 21808022 PMC3158162 source
Not checked in the free run.
May combine two claims.
Interpretationown dataDDB2 and XPC facilitate ATR and ATM recruitment to damage sites and affect their functional activation.
“These results were in agreement with the immunofluorescence data, showing that DDB2 and XPC facilitate ATR and ATM recruitment to the damage sites and affect their functional activation.”
Quote in the paperSubstantial claimMay combine two claims.
InterpretationcitationThese prior results support the idea that lesion processing is not required for γH2AX formation and checkpoint activation.
“These results support that lesion processing is not essential for γH2AX formation and checkpoint activation.”
Quote in the paperSubstantial claimThe quote only partly states this claim.
InterpretationreasoningThe checkpoint is not affected in cells defective in DDB2 and XPC function.
“Nonetheless, as the p53 level is up-regulated, we anticipate that the checkpoint is not affected in these cells.”
Quote in the paperSubstantial claim- Rests on an assumption: DNA damage triggers p53-dependent checkpoint arrest.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationAfter UV irradiation, RPA-coated single-stranded DNA recruits ATR to the UV damage site.
“It has been shown that in response to UV irradiation, RPA-coated single-stranded DNA (ssDNA) recruits ATR to the UV damage site [15, 16].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [15] Cortez D Unwind and slow down: checkpoint activation by helicase and polymerase uncoupling Genes Dev 19 2005 1007 1012 15879550 PMC1360198 source
Not checked in the free run.
- cites [16] Zou L Elledge SJ Sensing DNA damage through ATRIP recognition of RPA-ssDNA complexes Science 300 2003 1542 1548 12791985 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitationp21 is degraded upon lower doses of UV irradiation even though this lower level does not affect the cell cycle checkpoint.
“Other studies have shown that p21 is degraded upon lower dose of UV irradiation even though this lower level does not affect the cell cycle checkpoint [57, 59].”
Quote in the paperNot a substantial claim0 of 2 sources checked- cites [57] Bendjennat M Boulaire J Jascur T Brickner H Barbier V Sarasin A Fotedar A Fotedar R UV irradiation triggers ubiquitin-dependent degradation of p21(WAF1) to promote DNA repair Cell 114 2003 599 610 13678583 source
Not checked in the free run.
- cites [59] Al-Khalaf HH Hendrayani SF Aboussekhra A ATR controls the p21(WAF1/Cip1) protein up-regulation and apoptosis in response to low UV fluences Mol Carcinog 51 2012 930 938 21976111 source
Not checked in the free run.
May combine two claims.
Interpretationown dataThere is a defect in recruitment and/or phosphorylation of BRCA1 and Rad51 in XP-E and XP-C cells.
“This indicated an obvious defect in their recruitment and/or phosphorylation in these cells (Fig. 5A).”
Quote in the paperSubstantial claimMay combine two claims.
PremisecitationGM01389 cells defective in DDB2 carry a DDB2 mutation that impairs complex formation with DDB1 and consequently the formation of a functional DDB-XPC complex.
“DDB2-defective GM01389 cells carry mutation in DDB2 [52], which affects complex formation with DDB1 [58], and consequently the formation of functional DDB-XPC complex.”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [52] Nichols AF Itoh T Graham JA Liu W Yamaizumi M Linn S Human damage-specific DNA-binding protein p48 - Characterization of XPE mutations and regulation following UV irradiation J Biol Chem 275 2000 21422 21428 10777490 source
Not checked in the free run.
- cites [58] Jin J Arias EE Chen J Harper JW Walter JC A family of diverse Cul4-Ddb1-interacting proteins includes Cdt2, which is required for S phase destruction of the replication factor Cdt1 Mol Cell 23 2006 709 721 16949367 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
Premisecitationp21 is upregulated in p53-mediated G1 arrest.
“Several studies have shown that p21 is up regulated in p53-mediated G1 arrest.”
Quote in the paperNot a substantial claimProbably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationThe Mre11-Rad50-Nbs1 damage recognition complex enables checkpoint activation upstream of ATM recruitment to damage sites.
“This is akin to the DSB repair pathway in which the damage recognition complex, Mre11-Rad50-Nbs1, enables checkpoint activation upstream of ATM recruitment to the damage site [41].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Grenon M Gilbert C Lowndes NF Checkpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex Nat Cell Biol 3 2001 844 847 11533665 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationCdk2 is required for a p53-independent but Chk1- and Chk2-dependent cell cycle arrest.
“Recently, Chung and Bunz have shown that Cdk2 is required for a p53-independent, but Chk1- and Chk2-dependent cell cycle arrest [60]”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [60] Chung JH Bunz F Cdk2 is required for p53-independent G2/M checkpoint control PLoS Genet 6 2010 e1000863 20195506 PMC2829054 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn mismatch repair, lesion recognition factors and RPA-coated ssDNA recruit ATR to the damage site.
“However, in case of mismatch repair, ATR is recruited to the damage site by the lesion recognition factors and also by the RPA-coated ssDNA [40].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Wang Y Qin J MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation Proc Natl Acad Sci U S A 100 2003 15387 15392 14657349 PMC307577 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningKey protein factors from different DNA repair pathways physically associate with checkpoint sensors to coordinate DDR, and this appears to be a conserved mechanism for activating signaling cascades in response to diverse DNA damage.
“In essence, some of the key protein factors of different DNA repair pathways physically associate with checkpoint sensors to coordinately execute DDR, and this seems to represent a conserved mechanism for activating signaling cascades in response to diverse DNA damage.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationAfter cisplatin treatment, XPC physically interacts with ATM and participates in ATM activation.
“Furthermore, in response to cisplatin treatment, XPC physically interacts with ATM, and is involved in ATM activation [42].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [42] Colton SL Xu XS Wang YA Wang G The involvement of ataxia-telangiectasia mutated protein activation in nucleotide excision repair-facilitated cell survival with cisplatin treatment J Biol Chem 281 2006 27117 27125 16849332 source
Not checked in the free run.
May combine two claims.
Interpretationown dataDDB2 and XPC help assemble the ATR and ATM complex at UV damage sites and facilitate activation of the downstream DNA damage response cascade.
“We propose that DDB2 and XPC help assemble the ATR and ATM complex at the UV damage site and facilitate their activation to provoke the downstream cascade constituting the DNA damage response pathway.”
Quote in the paperSubstantial claimProbably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.
PremisecitationIn mismatch repair, ATR is recruited by MSH2 and the RPA-ATRIP complex; MSH2 interacts with ATR to form a signaling module and regulates phosphorylation of Chk1 and SMC1.
“Similarly, in the mismatch repair pathway, ATR is recruited by the early damage recognition factor, MSH2, and the RPA-ATRIP complex. MSH2 interacts with ATR to form a signaling module and regulates the phosphorylation of Chk1 and SMC1 [40].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [40] Wang Y Qin J MSH2 and ATR form a signaling module and regulate two branches of the damage response to DNA methylation Proc Natl Acad Sci U S A 100 2003 15387 15392 14657349 PMC307577 source
Not checked in the free run.
Probably not a substantial claim: may not pass S3 (load-bearing).
PremisecitationIn DSB repair, the MRN complex influences ATM recruitment.
“Additionally, in DSB repair pathway, the lesion recognition factor MRN complex influences ATM recruitment [41].”
Quote in the paperNot a substantial claim0 of 1 sources checked- cites [41] Grenon M Gilbert C Lowndes NF Checkpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex Nat Cell Biol 3 2001 844 847 11533665 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationUnrepaired fork gaps can become frank double-strand breaks.
“Unrepaired fork gaps can become frank DSB [24, 61, 62].”
Quote in the paperSubstantial claim0 of 3 sources checked- cites [24] Petermann E Helleday T Pathways of mammalian replication fork restart Nat Rev Mol Cell Biol 11 2010 683 687 20842177 source
Not checked in the free run.
- cites [61] Michel B Grompone G Flores MJ Bidnenko V Multiple pathways process stalled replication forks Proc Natl Acad Sci U S A 101 2004 12783 12788 15328417 PMC516472 source
Not checked in the free run.
- cites [62] Cox MM Goodman MF Kreuzer KN Sherratt DJ Sandler SJ Marians KJ The importance of repairing stalled replication forks Nature 404 2000 37 41 10716434 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningDDB2 and XPC act as upstream damage sensors and, through physical association with ATR and ATM, play a role in their functional activation via phosphorylation of target substrate proteins needed for HR repair and checkpoint pathways.
“Based on different elements revealed by this work, we propose that DDB2 and XPC act as upstream damage sensors, and through their physical association with ATR and ATM play a role in their functional activation via the well-established phosphorylation of their target substrate proteins needed for the HR repair and checkpoint pathway (Fig. 7).”
Quote in the paperSubstantial claim- The authors state this as an assumption: The DDB2/XPC complex represents the major sensor of UV damage.
Classified as probably not a substantial claim. May combine two claims.
PremisecitationBRCA1, BRCA2, and Rad51 participate in HR-mediated DNA repair and replication fork maintenance.
“BRCA1, BRCA2, and Rad51 are known to participate in HR-mediated DNA repair and replication fork maintenance [25, 26].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [25] Lundin C Schultz N Arnaudeau C Mohindra A Hansen LT Helleday T RAD51 is involved in repair of damage associated with DNA replication in mammalian cells J Mol Biol 328 2003 521 535 12706714 source
Not checked in the free run.
- cites [26] Chen JJ Silver D Cantor S Livingston DM Scully R BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway Cancer Res 59 1999 1752s 1756s 10197592
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationSpontaneous HR is promoted by collapsed replication forks caused by endogenous DNA single-strand breaks.
“It has been established that spontaneous HR is promoted by collapsed replication forks that are caused by endogenous DNA SSB [24, 28].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [24] Petermann E Helleday T Pathways of mammalian replication fork restart Nat Rev Mol Cell Biol 11 2010 683 687 20842177 source
Not checked in the free run.
- cites [28] Falck J Mailand N Syljuasen RG Bartek J Lukas J The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis Nature 410 2001 842 847 11298456 source
Not checked in the free run.
Classified as probably not a substantial claim.
PremisecitationBoth the ATR-Chk1 and ATM-Chk2 pathways regulate HR-mediated repair of collapsed replication forks.
“Moreover, both the ATR-Chk1 and ATM-Chk2 pathways regulate HR-mediated repair of collapsed replication forks [27, 28].”
Quote in the paperSubstantial claim0 of 2 sources checked- cites [27] Sorensen CS Hansen LT Dziegielewski J Syljuasen RG Lundin C Bartek J Helleday T The cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair Nat Cell Biol 7 2005 195 201 15665856 source
Not checked in the free run.
- cites [28] Falck J Mailand N Syljuasen RG Bartek J Lukas J The ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis Nature 410 2001 842 847 11298456 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningDDB2 and XPC function upstream of ATR and ATM recruitment and are unique to the ATR-Chk1-BRCA1 and ATM-Chk2-BRCA1 axis of checkpoint and repair.
“Furthermore, it also confirms that DDB2 and XPC function upstream of ATR and ATM recruitment and are unique to ATR-Chk1-BRCA1 and ATM-Chk2-BRCA1 axis of checkpoint and repair.”
Quote in the paperSubstantial claimClassified as probably not a substantial claim. May combine two claims.
PremisecitationATR and ATM allow H2AX phosphorylation and spreading at damage sites, which changes chromatin structure near the damage and executes DNA repair through the HR pathway.
“Additionally, it is well established that ATR and ATM allow H2AX phosphorylation and spreading at the damage site, which changes the chromatin structure near the damage site and executes DNA repair through the HR pathway [21-23, 26, 63].”
Quote in the paperSubstantial claim0 of 5 sources checked- cites [21] Savic V B Yin Maas NL Bredemeyer AL Carpenter AC Helmink BA Yang-Iott KS Sleckman BP Bassing CH Formation of dynamic gamma-H2AX domains along broken DNA strands is distinctly regulated by ATM and MDC1 and dependent upon H2AX densities in chromatin Mol Cell 34 2009 298 310 19450528 PMC2744111 source
Not checked in the free run.
- cites [22] Xie A Odate S Chandramouly G Scully R H2AX post-translational modifications in the ionizing radiation response and homologous recombination Cell Cycle 9 2010 3602 3610 20703100 PMC2980696 source
Not checked in the free run.
- cites [23] Chen J Ataxia telangiectasia-related protein is involved in the phosphorylation of BRCA1 following deoxyribonucleic acid damage Cancer Res 60 2000 5037 5039 11016625
Not checked in the free run.
- cites [26] Chen JJ Silver D Cantor S Livingston DM Scully R BRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway Cancer Res 59 1999 1752s 1756s 10197592
Not checked in the free run.
- cites [63] Chanoux RA Yin B Urtishak KA Asare A Bassing CH Brown EJ ATR and H2AX cooperate in maintaining genome stability under replication stress J Biol Chem 284 2009 5994 6003 19049966 PMC2645842 source
Not checked in the free run.
May combine two claims.
InterpretationreasoningSingle-strand and double-strand breaks will be repaired through the ATR-Chk1- and ATM-Chk2-mediated HR pathway.
“Based on our results that DDB2 and XPC are required for the activation of both ATR-Chk1 and ATM-Chk2 pathways, we anticipate that the SSB and DSB will be repaired through ATR-Chk1- and ATM-Chk2 mediated HR pathway.”
Quote in the paperSubstantial claim
The paper relies on this without support.
It is not clearly established whether UV-damage recognition factors directly influence ATR and ATM recruitment and phosphorylation.
“However, whether UV-damage recognition factors directly influence ATR and ATM recruitment and their phosphorylation is not clearly established.”
The paper relies on this without support.
Studies supporting NER-dependent checkpoint activation do not show how and when ATR and ATM are recruited to damage sites and phosphorylate downstream substrates.
“Even though these studies support that the checkpoint activation induced by UV irradiation requires a functional NER apparatus, these studies do not show how and when ATR and ATM are recruited to the damage site and result in phosphorylation of downstream substrates.”
The paper relies on this without support.
Whether NER proteins play a direct role in ATR and ATM recruitment has not been shown.
“Whether the NER proteins play any direct role in ATR and ATM recruitment, however, has not been shown.”
The paper relies on this without support.
It is unclear whether NER lesion recognition factors and DDR kinases are co-recruited or cross-recruited to UV damage sites.
“While the lesion recognition NER factors as well as DDR kinases promptly congregate at the UV damage sites, it is unclear if the factors of two seemingly different pathways, co-recruited or cross-recruited to the damage site.”
The paper relies on this without support.
XPC-defective cells are impaired in the functional DDB-XPC complex.
“Similarly, XPC-defective cells are impaired in the functional DDB-XPC complex.”
The paper relies on this without support.
Chk1 and Chk2 phosphorylation is required for cell cycle arrest by triggering Cdc25A degradation.
“which is required for cell cycle arrest by triggering Cdc25A degradation.”
The paper relies on this without support.
DNA damage triggers p53-dependent checkpoint arrest.
“As DNA damage triggers p53-dependent checkpoint arrest”
The authors state this as an assumption.
The DDB2/XPC complex represents the major sensor of UV damage.
“Essentially, our work is built on the premise that DDB2/XPC complex represents the major sensor of UV-damage.”
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
NER recruits ATR to UV-damage sites and activates ATR in G1 phase but not in S phase.
“Consistently, NER recently was found to recruit ATR to the UV-damage sites and to activate ATR in G1-phase but not in S-phase 73–76.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [74]
UVR-induced DNA damage and replication stress also activates ATM, which in turn phosphorylates H2AX.
“Recently, we and others have shown that UVR-induced DNA damage and replication stress also activates ATM [39–42], which in turn phosphorylates H2AX [40;41].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [41]
DDB2 and XPC influence ATR and ATM recruitment to the damage site and promote their activation by phosphorylation.
“Moreover, we showed that DDB2 and XPC influence ATR and ATM recruitment to the damage site and promote their activation by phosphorylation [41].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [41]
ATR and ATM physically and functionally interact with XPC.
“Our previous study demonstrated that ATR and ATM physically and functionally interact with XPC.”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [41]
DDB2 and XPC regulate ATR and ATM recruitment and signaling following UVR exposures.
“Additionally, DDB2 and XPC regulate ATR and ATM recruitment and signaling following UVR exposures [41].”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [41]
ATR and ATM recruitment is dependent on the assembly of functional DNA repair proteins.
“We have previously demonstrated that ATR and ATM recruitment is dependent on the assembly of functional DNA repair proteins”
From ATR- and ATM-Mediated DNA Damage Response Is Dependent on Excision Repair Assembly during G1 but Not in S Phase of Cell Cycle (2016) · cites this paper as [41]
ATM and ATR appear unnecessary for recruiting DDB2 and XPC to UV-damaged sites and for NER repair of CPDs and 6-4PPs.
“ATM and ATR seem to be not essential for the recruitment of DDB2 and XPC to UV-damage sites and the NER repair of CPD and 6–4PP [203]”
From Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress (2014) · cites this paper as [203]
Cites
The DNA-damage response in human biology and disease
Jackson, S. P., & Bartek, J. (2009) · Nature · doi:10.1038/nature08467 · Cited by 6,092 · cited 1× · see citing works
“The DNA damage response (DDR) pathway plays a critical role in maintaining genomic stability and preventing carcinogenesis [1].”
BackgroundDNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation
Bakkenist, C. J., & Kastan, M. B. (2003) · Nature · doi:10.1038/nature01368 · Cited by 3,466 · cited 1× · see citing works
“In contrast, ATM phosphorylation at S1981 is strictly damage-dependent [53].”
BackgroundMolecular Mechanisms of Mammalian DNA Repair and the DNA Damage Checkpoints
Sancar, A., Lindsey-Boltz, L. A., Ünsal-Kaçmaz, K., & Linn, S. (2004) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.73.011303.073723 · Cited by 3,317 · cited 1× · see citing works
“The phosphoinositide-3-kinase-like kinases family of protein kinases including ATR (Ataxia telangiectasia- and Rad3- related) and ATM (Ataxia telangiectasia mutated) are the principal checkpoint kinases activated by DNA damage [13, 14].”
BackgroundCell-cycle checkpoints and cancer
Kastan, M. B., & Bartek, J. (2004) · Nature · doi:10.1038/nature03097 · Cited by 2,836 · cited 1× · see citing works
“Growing evidence suggests that ATR, ATM, Chk1, Chk2, and BRCA1 are multi-organ tumor suppressor genes found mutated in various cancers [66].”
BackgroundRequirement for p53 and p21 to Sustain G <sub>2</sub> Arrest After DNA Damage
Bunz, F., Dutriaux, A., Lengauer, C., Waldman, T., Zhou, S., Brown, J. P., Sedivy, J. M., Kinzler, K. W., & Vogelstein, B. (1998) · Science · doi:10.1126/science.282.5393.1497 · Cited by 2,803 · cited 2× · see citing works
“It has been shown that following damage induction p53 functions to arrest cells at either G1/S or G2/M boundary [54, 55].”
BackgroundSensing DNA Damage Through ATRIP Recognition of RPA-ssDNA Complexes
Zou, L., & Elledge, S. J. (2003) · Science · doi:10.1126/science.1083430 · Cited by 2,693 · cited 3× · see citing works
“As ATR is recruited by the RPA-ATRIP complex [15, 16] and influenced by DDB2 and XPC, it is possible that these NER factors also associate with the RPA-ATRIP complex, and thereby affect ATR and ATM recruitment.”
BackgroundDulić, V., Kaufmann, W. K., Wilson, S. J., Tisty, T. D., Lees, E., Harper, J. W., Elledge, S. J., & Reed, S. I. (1994) · Cell · doi:10.1016/0092-8674(94)90379-4 · Cited by 1,465 · see citing works
Sancar, A. (1996) · Annual Review of Biochemistry · doi:10.1146/annurev.bi.65.070196.000355 · Cited by 1,131 · cited 1× · see citing works
“The resulting gap is filled by repair synthesis, and finally the nick is ligated to complete NER [2, 10].”
BackgroundMolecular mechanism of nucleotide excision repair
de Laat, W. L., Jaspers, N. G. J., & Hoeijmakers, J. H. J. (1999) · Genes & Development · doi:10.1101/gad.13.7.768 · Cited by 1,122 · cited 2× · see citing works
“The resulting gap is filled by repair synthesis, and finally the nick is ligated to complete NER [2, 10].”
BackgroundThe ATM-Chk2-Cdc25A checkpoint pathway guards against radioresistant DNA synthesis
Falck, J., Mailand, N., Syljuåsen, R. G., Bartek, J., & Lukas, J. (2001) · Nature · doi:10.1038/35071124 · Cited by 1,085 · cited 8× · see citing works
“repair pathway [27, 28], where both H2AX and BRCA1 phosphorylations have been known to play a facilitative role [22, 26].”
BackgroundInfluentialThe importance of repairing stalled replication forks
Cox, M. M., Goodman, M. F., Kreuzer, K. N., Sherratt, D. J., Sandler, S. J., & Marians, K. J. (2000) · Nature · doi:10.1038/35003501 · Cited by 1,044 · cited 8× · see citing works
“If not repaired, stalled fork gaps can evolve into DSB [24].”
BackgroundInfluentialDNA damage checkpoints: from initiation to recovery or adaptation
Bartek, J., & Lukas, J. (2007) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2007.02.009 · Cited by 784 · cited 1× · see citing works
“ATM phosphorylates the checkpoint kinase Chk2, which also triggers degradation of Cdc25A phosphatases to delay the cell cycle [20].”
BackgroundDirect Activation of the ATM Protein Kinase by the Mre11/Rad50/Nbs1 Complex
Lee, J.-H., & Paull, T. T. (2004) · Science · doi:10.1126/science.1091496 · Cited by 762 · cited 1× · see citing works
“In response to DSB, the lesion recognition factor Mre11-Rad50-Nbs1 (MRN) complex helps the recruitment of ATM to the damage site and its activation by phosphorylation [29].”
BackgroundNucleotide excision repair and human syndromes
de Boer, J., & Hoeijmakers, J. H. J. (2000) · Carcinogenesis · doi:10.1093/carcin/21.3.453 · Cited by 674 · cited 2× · see citing works
“carcinoma, head and neck cancer, colorectal cancer, and leukemia [11, 12, 67-69].”
BackgroundThe cell-cycle checkpoint kinase Chk1 is required for mammalian homologous recombination repair
Sørensen, C. S., Hansen, L. T., Dziegielewski, J., Syljuåsen, R. G., Lundin, C., Bartek, J., & Helleday, T. (2005) · Nature Cell Biology · doi:10.1038/ncb1212 · Cited by 666 · cited 3× · see citing works
“repair pathway [27, 28], where both H2AX and BRCA1 phosphorylations have been known to play a facilitative role [22, 26].”
BackgroundJin, J., Arias, E. E., Chen, J., Harper, J. W., & Walter, J. C. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.08.010 · Cited by 632 · cited 6× · see citing works
“DDB2-defective GM01389 cells carry mutation in DDB2 [52], which affects complex formation with DDB1 [58], and consequently the formation of functional DDB-XPC complex.”
BackgroundInfluentialATM and ATR: networking cellular responses to DNA damage
Shiloh, Y. (2001) · Current Opinion in Genetics & Development · doi:10.1016/s0959-437x(00)00159-3 · Cited by 601 · cited 1× · see citing works
“The phosphoinositide-3-kinase-like kinases family of protein kinases including ATR (Ataxia telangiectasia- and Rad3- related) and ATM (Ataxia telangiectasia mutated) are the principal checkpoint kinases activated by DNA damage [13, 14].”
BackgroundUV-Induced Ubiquitylation of XPC Protein Mediated by UV-DDB-Ubiquitin Ligase Complex
Sugasawa, K., Okuda, Y., Saijo, M., Nishi, R., Matsuda, N., Chu, G., Mori, T., Iwai, S., Tanaka, K., Tanaka, K., et al. (2005) · Cell · doi:10.1016/j.cell.2005.02.035 · Cited by 576 · cited 1× · see citing works
“The DDB1-CUL4-ROC1 complex ubiquitylates XPC, which may enhance DNA binding by XPC and promotes NER [6, 7].”
BackgroundMammalian G1- and S-phase checkpoints in response to DNA damage
Bártek, J., & Lukas, J. (2001) · Current Opinion in Cell Biology · doi:10.1016/s0955-0674(00)00280-5 · Cited by 573 · cited 1× · see citing works
“It has been shown that following damage induction p53 functions to arrest cells at either G1/S or G2/M boundary [54, 55].”
BackgroundSubpathways of nucleotide excision repair and their regulation
Hanawalt, P. C. (2002) · Oncogene · doi:10.1038/sj.onc.1206096 · Cited by 447 · cited 1× · see citing works
“One sub-pathway of NER, global genome NER (GG-NER), removes damage from the entire genome, whereas DNA damage in the transcribed strand of active genes is preferentially eliminated by transcription-coupled NER (TC-NER) [3].”
BackgroundA multistep damage recognition mechanism for global genomic nucleotide excision repair
Sugasawa, K., Okamoto, T., Shimizu, Y., Masutani, C., Iwai, S., & Hanaoka, F. (2001) · Genes & Development · doi:10.1101/gad.866301 · Cited by 435 · cited 2× · see citing works
“In turn, XPC helps in recruiting XPA, XPG, and TFIIH components that enable opening of the DNA helix around the damage site to form a bubble [8].”
BackgroundChk1 mediates S and G2 arrests through Cdc25A degradation in response to DNA-damaging agents
Xiao, Z., Chen, Z., Gunasekera, A. H., Sowin, T. J., Rosenberg, S. H., Fesik, S., & Zhang, H. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300229200 · Cited by 388 · cited 1× · see citing works
“Activated Chk1 phosphorylates Cdc25 phosphatases to inhibit their function, and the cells delay progression through the cell cycle [17].”
BackgroundMarti, T. M., Hefner, E., Feeney, L., Natale, V., & Cleaver, J. E. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0603779103 · Cited by 359 · cited 2× · see citing works
“The UV damaged foci exhibited the distinct phosphorylation of H2AX, a recognized molecular marker of damage response initiation [19, 32, 35-37].”
BackgroundPathways of mammalian replication fork restart
Petermann, E., & Helleday, T. (2010) · Nature Reviews Molecular Cell Biology · doi:10.1038/nrm2974 · Cited by 340 · cited 11× · see citing works
“If not repaired, stalled fork gaps can evolve into DSB [24].”
BackgroundInfluentialMultiple pathways process stalled replication forks
Michel, B., Grompone, G., Florès, M.-J., & Bidnenko, V. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0401586101 · Cited by 322 · cited 8× · see citing works
“If not repaired, stalled fork gaps can evolve into DSB [24].”
BackgroundInfluentialIn vivo recruitment of XPC to UV-induced cyclobutane pyrimidine dimers by the DDB2 gene product
Fitch, M. E., Nakajima, S., Yasui, A., & Ford, J. M. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m307254200 · Cited by 260 · cited 2× · see citing works
“In GG-NER, damage is recognized by the UV-DDB (DDB1 and DDB2) and XPC-RAD23B complexes [4, 5].”
BackgroundUV Irradiation Triggers Ubiquitin-Dependent Degradation of p21WAF1 to Promote DNA Repair
Bendjennat, M., Boulaire, J., Jascur, T., Brickner, H., Barbier, V., Sarasin, A., Fotedar, A., & Fotedar, R. (2003) · Cell · doi:10.1016/j.cell.2003.08.001 · Cited by 248 · cited 2× · see citing works
“Other studies have shown that p21 is degraded upon lower dose of UV irradiation even though this lower level does not affect the cell cycle checkpoint [57, 59].”
BackgroundResultWakasugi, M., Kawashima, A., Morioka, H., Linn, S., Sancar, A., Mori, T., Nikaido, O., & Matsunaga, T. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.c100610200 · Cited by 227 · cited 2× · see citing works
“In GG-NER, damage is recognized by the UV-DDB (DDB1 and DDB2) and XPC-RAD23B complexes [4, 5].”
BackgroundBRCA1, BRCA2, and Rad51 operate in a common DNA damage response pathway.
Chen, J. J., Silver, D. P., Cantor, S., Livingston, D. M., & Scully, R. (1999) · PubMed · Cited by 217 · see citing works
Hanasoge, S., & Ljungman, M. (2007) · Carcinogenesis · doi:10.1093/carcin/bgm157 · Cited by 216 · cited 2× · see citing works
“The UV damaged foci exhibited the distinct phosphorylation of H2AX, a recognized molecular marker of damage response initiation [19, 32, 35-37].”
BackgroundAnindya, R., Aygün, O., & Svejstrup, J. Q. (2007) · Molecular Cell · doi:10.1016/j.molcel.2007.10.008 · Cited by 215 · cited 1× · see citing works
“Fractionation of extracts, isolation of chromatin-bound proteins, and immunoprecipitation were performed essentially as described [19, 45, 46].”
MethodSavic, V., Yin, B., Maas, N. L., Bredemeyer, A. L., Carpenter, A. C., Helmink, B. A., Yang-Iott, K. S., Sleckman, B. P., & Bassing, C. H. (2009) · Molecular Cell · doi:10.1016/j.molcel.2009.04.012 · Cited by 204 · cited 1× · see citing works
“Additionally, it is well established that ATR and ATM allow H2AX phosphorylation and spreading at the damage site, which changes the chromatin structure near the damage site and executes DNA repair through the HR pathway [21-23, 26, 63].”
BackgroundCheckpoint activation in response to double-strand breaks requires the Mre11/Rad50/Xrs2 complex
Grenon, M., Gilbert, C., & Lowndes, N. F. (2001) · Nature Cell Biology · doi:10.1038/ncb0901-844 · Cited by 184 · cited 2× · see citing works
“This is akin to the DSB repair pathway in which the damage recognition complex, Mre11-Rad50-Nbs1, enables checkpoint activation upstream of ATM recruitment to the damage site [41].”
BackgroundWang, Y., & Qin, J. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2536810100 · Cited by 181 · cited 3× · see citing works
“MSH2 interacts with ATR to form a signaling module and regulates the phosphorylation of Chk1 and SMC1 [40].”
BackgroundInfluentialReardon, J. T., & Sancar, A. (2003) · Genes & Development · doi:10.1101/gad.1131003 · Cited by 179 · cited 2× · see citing works
“carcinoma, head and neck cancer, colorectal cancer, and leukemia [11, 12, 67-69].”
BackgroundEl-Mahdy, M. A., Zhu, Q., Wang, Q.-E., Wani, G., Prætorius-Ibba, M., & Wani, A. A. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511834200 · Cited by 151 · cited 1× · see citing works
“Lesions of the genomic DNA in native cellular environment were induced by micro-pore local UV irradiation and their detection was performed by dual immunofluorescent staining by our established methods [47, 48].”
MethodSelf-citationMatsumoto, M., Yaginuma, K., Igarashi, A., Imura, M., Hasegawa, M., Iwabuchi, K., Date, T., Mori, T., Ishizaki, K., Yamashita, K., et al. (2007) · Journal of Cell Science · doi:10.1242/jcs.03391 · Cited by 138 · cited 3× · see citing works
“The co-localization of γ-H2AX with CPD and 6-4PP has been used to demonstrate the participation of ATR to the UV damage site [35].”
BackgroundMethodHuman Damage-specific DNA-binding Protein p48
Nichols, A. F., Itoh, T., Graham, J. A., Liu, W., Yamaizumi, M., & Linn, S. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m000960200 · Cited by 137 · see citing works
Chavanne, F., Broughton, B. C., Pietra, D., Nardò, T., Browitt, A., Lehmann, A. R., & Stefanini, M. (2000) · PubMed · Cited by 133 · see citing works
ATR and H2AX cooperate in maintaining genome stability under replication stress
Chanoux, R. A., Yin, B., Urtishak, K. A., Asare, A., Bassing, C. H., & Brown, E. J. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m806739200 · Cited by 130 · cited 1× · see citing works
“Additionally, it is well established that ATR and ATM allow H2AX phosphorylation and spreading at the damage site, which changes the chromatin structure near the damage site and executes DNA repair through the HR pathway [21-23, 26, 63].”
BackgroundYajima, H., Lee, K.-J., Zhang, S., Kobayashi, J., & Chen, B. P. C. (2009) · Journal of Molecular Biology · doi:10.1016/j.jmb.2008.11.036 · Cited by 124 · cited 2× · see citing works
“Furthermore, SSB can also form upon processing of UV-lesions [18, 19].”
BackgroundDNA nucleotide excision repair-dependent signaling to checkpoint activation
Marini, F., Nardo, T., Giannattasio, M., Minuzzo, M., Stefanini, M., Plevani, P., & Falconi, M. M. (2006) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0605446103 · Cited by 114 · cited 1× · see citing works
“However, several studies reported that lesion processing by NER factors might be an essential step in γH2AX foci formation [35-39].”
BackgroundRAD51 is involved in repair of damage associated with DNA replication in mammalian cells
Lundin, C., Schultz, N., Arnaudeau, C., Mohindra, A., Hansen, L. T., & Helleday, T. (2003) · Journal of Molecular Biology · doi:10.1016/s0022-2836(03)00313-9 · Cited by 113 · cited 3× · see citing works
“BRCA1, BRCA2, and Rad51 are known to participate in HR-mediated DNA repair and replication fork maintenance [25, 26].”
BackgroundRapic-Otrin, V. (2003) · Human Molecular Genetics · doi:10.1093/hmg/ddg174 · Cited by 113 · cited 1× · see citing works
“To address this, we examined the ATR and ATM immunofluorescent localization to UV damage sites in NHF and patient-derived cells defective in DDB2 (XP-E) or XPC (XP-C) functions [50-52].”
BackgroundPhysical and functional interactions between nucleotide excision repair and DNA damage checkpoint
Giannattasio, M., Lazzaro, F., Longhese, M. P., Plevani, P., & Muzi‐Falconi, M. (2004) · The EMBO Journal · doi:10.1038/sj.emboj.7600051 · Cited by 113 · cited 1× · see citing works
“In yeast, UV-induced DNA damage results in checkpoint activation independent of NER lesion processing [33, 34].”
BackgroundLi, J., Wang, Q.-E., Zhu, Q., El-Mahdy, M. A., Wani, G., Prætorius-Ibba, M., & Wani, A. A. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-1115 · Cited by 106 · cited 1× · see citing works
“The DDB1-CUL4-ROC1 complex ubiquitylates XPC, which may enhance DNA binding by XPC and promotes NER [6, 7].”
BackgroundSelf-citationLuijsterburg, M. S., Goedhart, J., Moser, J., Kool, H., Geverts, B., Houtsmuller, A. B., Mullenders, L. H. F., Vermeulen, W., & van Driel, R. (2007) · Journal of Cell Science · doi:10.1242/jcs.008367 · Cited by 105 · cited 1× · see citing works
“The DDB complex initially recognizes the CPD lesions and recruits XPC [4, 5, 8, 9], whereas XPC can independently recognize 6-4PP lesions [5].”
BackgroundCdk2 is required for p53-independent G2/M checkpoint control
Chung, J. H., & Bunz, F. (2010) · PLoS Genetics · doi:10.1371/journal.pgen.1000863 · Cited by 105 · cited 1× · see citing works
“Recently, Chung and Bunz have shown that Cdk2 is required for a p53-independent, but Chk1- and Chk2dependent cell cycle arrest [60], raising the possibility that DDB2 and XPC might influence this axis of checkpoint signaling pathway.”
BackgroundModulation of Nucleotide Excision Repair by Mammalian SWI/SNF Chromatin-remodeling Complex
Zhao, Q., Wang, Q.-E., Ray, A., Wani, G., Han, C., Milum, K., & Wani, A. A. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.044982 · Cited by 102 · cited 2× · see citing works
“quantitation of dimers in DNA isolated from cells at different post-irradiation times as described earlier [44, 45, 49].”
MethodSelf-citationVrouwe, M. G., Pines, A., Overmeer, R. M., Hanada, K., & Mullenders, L. H. F. (2011) · Journal of Cell Science · doi:10.1242/jcs.075325 · Cited by 100 · cited 1× · see citing works
“Furthermore, Vrouwe et al reported that UV-induced photolesions results in checkpoint activation in NER-dependent and -independent pathways [31].”
BackgroundWang, Q. (2003) · DNA repair · doi:10.1016/s1568-7864(03)00002-8 · Cited by 96 · cited 1× · see citing works
“Lesions of the genomic DNA in native cellular environment were induced by micro-pore local UV irradiation and their detection was performed by dual immunofluorescent staining by our established methods [47, 48].”
MethodChen, J. (2000) · PubMed · Cited by 94 · see citing works
Shell, S. M., Li, Z., Shkriabai, N., Kvaratskhelia, M., Brosey, C., Serrano, M. A., Chazin, W. J., Musich, P. R., & Zou, Y. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.000745 · Cited by 86 · cited 1× · see citing works
“Our finding that ATR and ATM associate with XPC in response to UV damage is in agreement with others data showing ATR interacts with XPA upon irradiation [64], and phosphorylates XPA [65].”
ResultWu, X., Shell, S. M., Yang, Z., & Zou, Y. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-3403 · Cited by 85 · cited 5× · see citing works
“Patients deficient in XPA, XPB, XPC, XPD, XPF, XPG and DDB2 genes (XP) display over 2,000-fold increased incidence rates of skin cancer.”
ResultInfluentialUnwind and slow down: checkpoint activation by helicase and polymerase uncoupling: Figure 1.
Cortez, D. (2005) · Genes & Development · doi:10.1101/gad.1316905 · Cited by 84 · cited 3× · see citing works
“As ATR is recruited by the RPA-ATRIP complex [15, 16] and influenced by DDB2 and XPC, it is possible that these NER factors also associate with the RPA-ATRIP complex, and thereby affect ATR and ATM recruitment.”
BackgroundGil, J., Ramsey, D., Stembalska, A., Karpiński, P., Pesz, K. A., Łaczmańska, I., Leszczyński, P., Grzebieniak, Z., & Sasiadek, M. M. (2011) · Molecular Biology Reports · doi:10.1007/s11033-011-0767-5 · Cited by 84 · see citing works
Sertic, S., Pizzi, S., Cloney, R., Lehmann, A. R., Marini, F., Plevani, P., & Muzi-Falconi, M. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1108547108 · Cited by 80 · cited 1× · see citing works
“However, several studies reported that lesion processing by NER factors might be an essential step in γH2AX foci formation [35-39].”
BackgroundWani, A. A., D’Ambrosio, S. M., & Alvi, N. K. (1987) · Photochemistry and Photobiology · doi:10.1111/j.1751-1097.1987.tb04798.x · Cited by 77 · cited 2× · see citing works
“quantitation of dimers in DNA isolated from cells at different post-irradiation times as described earlier [44, 45, 49].”
MethodSelf-citationASF1A and ATM regulate H3K56-mediated cell-cycle checkpoint recovery in response to UV irradiation
Battu, A., Ray, A., & Wani, A. A. (2011) · Nucleic Acids Research · doi:10.1093/nar/gkr523 · Cited by 72 · cited 3× · see citing works
“quantitation of dimers in DNA isolated from cells at different post-irradiation times as described earlier [44, 45, 49].”
MethodSelf-citationRay, A., Mir, S. N., Wani, G., Zhao, Q., Battu, A., Zhu, Q., Wang, Q.-E., & Wani, A. A. (2009) · Molecular and Cellular Biology · doi:10.1128/mcb.00503-09 · Cited by 71 · cited 8× · see citing works
“The UV damaged foci exhibited the distinct phosphorylation of H2AX, a recognized molecular marker of damage response initiation [19, 32, 35-37].”
BackgroundMethodInfluentialSelf-citationRecruitment of DNA damage checkpoint proteins to damage in transcribed and nontranscribed sequences
Jiang, G., & Sancar, A. (2006) · Molecular and Cellular Biology · doi:10.1128/mcb.26.1.39-49.2006 · Cited by 70 · cited 1× · see citing works
“Jiang and Sancar showed direct binding of ATR to the damaged DNA without lesion processing, raising the possibility that ATR may activate the checkpoint signaling directly [30].”
BackgroundColton, S. L., Xu, X. S., Wang, Y. A., & Wang, G. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602826200 · Cited by 65 · cited 2× · see citing works
“In accord, XPC has been shown to associate with ATM after cisplatin treatment, where NER is also the predominant pathway of DNA repair [42].”
BackgroundDNA repair mechanisms protect our genome from carcinogenesis
Moraes, M. C. S. (2012) · Frontiers in Bioscience · doi:10.2741/3992 · Cited by 64 · cited 1× · see citing works
“carcinoma, head and neck cancer, colorectal cancer, and leukemia [11, 12, 67-69].”
BackgroundOh, K.-S., Bustin, M., Mazur, S. J., Appella, E., & Kraemer, K. H. (2011) · DNA Repair · doi:10.1016/j.dnarep.2010.09.004 · Cited by 60 · cited 2× · see citing works
“The UV damaged foci exhibited the distinct phosphorylation of H2AX, a recognized molecular marker of damage response initiation [19, 32, 35-37].”
BackgroundXie, A., Odate, S., Chandramouly, G., & Scully, R. A. (2010) · Cell Cycle · doi:10.4161/cc.9.17.12884 · Cited by 59 · cited 3× · see citing works
“Moreover, ATR- and ATM-mediated phosphorylation of BRCA1 and H2AX [22, 23] is required for S and G2/M phase checkpoints and homologous recombination (HR)-mediated DNA repair during S and G2 phases.”
BackgroundVenkatachalam, S., Denissenko, M. F., & Wani, A. A. (1997) · Oncogene · doi:10.1038/sj.onc.1200890 · Cited by 50 · cited 1× · see citing works
“HeLa-60 cells expressing FLAG-DDB2 and HA-XPC, and normal human fibroblasts (NHF, OSU-2) were generated in our laboratory [43].”
MethodSelf-citationHernández‐Boluda, J. C., Pereira, A., Cervantes, F., Álvarez‐Larrán, A., Collado, M., Such, E., Arilla, M.-J., Boqué, C., Xicoy, B., Maffioli, M., et al. (2012) · Blood · doi:10.1182/blood-2012-02-411215 · Cited by 38 · cited 1× · see citing works
“carcinoma, head and neck cancer, colorectal cancer, and leukemia [11, 12, 67-69].”
BackgroundZhang, H., Taylor, J., & Siede, W. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m300061200 · Cited by 24 · cited 1× · see citing works
“In yeast, UV-induced DNA damage results in checkpoint activation independent of NER lesion processing [33, 34].”
BackgroundAl‐Khalaf, H. H., Hendrayani, S., & Aboussekhra, A. (2012) · Molecular Carcinogenesis · doi:10.1002/mc.20864 · Cited by 13 · cited 1× · see citing works
“Other studies have shown that p21 is degraded upon lower dose of UV irradiation even though this lower level does not affect the cell cycle checkpoint [57, 59].”
Background
Flagged first, then by citations
3 of the 72 references couldn’t be matched to a known paper.
Cited by
Sorted by citations
Yan, S., Sorrell, M., & Berman, Z. (2014) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-014-1666-4 · Cited by 247 · see citing works
Regulation of DNA Repair Mechanisms: How the Chromatin Environment Regulates the DNA Damage Response
Stadler, J., & Richly, H. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081715 · Cited by 110 · see citing works
“Recruitment of both kinases is dependent on the damage recognition factors XPC, DDB2, and XPA only during the G1 phase [37,38].”
BackgroundThe emerging role of deubiquitinating enzymes in genomic integrity, diseases, and therapeutics
He, M., Zhou, Z., Shah, A. A., Zou, H., Tao, J., Chen, Q., & Wan, Y. (2016) · Cell & Bioscience · doi:10.1186/s13578-016-0127-1 · Cited by 106 · see citing works
“DDB2, associates with DDB1, to recruit XPC to chromatin, and also facilitates the recruitment of cullin 4A/B-RING ubiquitin ligases which ubiquitinate various acceptor proteins including DDB2 and XPC [96].”
BackgroundInfluentialAutophagy in UV Damage Response
Sample, A., & He, Y. (2016) · Photochemistry and Photobiology · doi:10.1111/php.12691 · Cited by 90 · see citing works
“been shown to facilitate the recruitment of ATM and ATR to sites of DNA damage and promote the activation of cell cycle arrest pathways (76).”
BackgroundFaltermann, S., Zucchi, S., Kohler, E., et al. (2014) · Aquatic Toxicology · doi:10.1016/j.aquatox.2014.01.018 · Cited by 79 · see citing works
“XPC is a key factor in NER and together with DDB-2 recruiting machinery to eliminate DNA damage (Ray et al., 2013).”
BackgroundProtective mechanisms and responses of micro-fungi towards ultraviolet-induced cellular damage
Wong, H. J., Mohamad‐Fauzi, N., Rizman‐Idid, M., Convey, P., & Alias, S. A. (2018) · Polar Science · doi:10.1016/j.polar.2018.10.001 · Cited by 67 · see citing works
“The NER pathway is characterized by incision on both sides of the damaged DNA strand, resulting in a 24–32 bp short oligonucleotide fragment being removed (Ray et al., 2013).”
Swope, V., Alexander, C., Starner, R., Schwemberger, S., Babcock, G., & Abdel‐Malek, Z. A. (2014) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12252 · Cited by 67 · see citing works
“Phosphorylation of p53 on Ser15 is induced by ATR and ATM and is crucial for GGR (Banin et al., 1998; Canman et al., 1998; Kastan and Bartek, 2004).”
BackgroundInfluentialCai, Q., Fu, L., Wang, Z., Gan, N., Dai, X., & Wang, Y. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.m114.558510 · Cited by 57 · see citing works
“2 The abbreviations used are: NER, nucleotide excision repair; CPD, cyclobutane pyrimidine dimer; NRMT, N-terminal RCC1 methyltransferase; XPC, xeroderma pigmentosum complementation group C; ATM, ataxia telangiectasia mutated; ATR, ATM and Rad 3-related; ESI, electrospray ionization; CENP-B, centromere protein B.”
BackgroundInfluentialMolecular signaling cascades involved in nonmelanoma skin carcinogenesis
Feehan, R. P., & Shantz, L. M. (2016) · Biochemical Journal · doi:10.1042/bcj20160471 · Cited by 54 · see citing works
Repair of UVB-induced DNA damage is reduced in melanoma due to low XPC and global genome repair
Budden, T., Davey, R. J., Vilain, R. E., Ashton, K. A., Braye, S. G., Beveridge, N. J., & Bowden, N. A. (2016) · Oncotarget · doi:10.18632/oncotarget.10902 · Cited by 52 · see citing works
ROS regulation in gliomas: implications for treatment strategies
Yang, Y.-C., Zhu, Y., Sun, S.-J., Zhao, C.-J., Bai, Y., Wang, J., & Ma, L. (2023) · Frontiers in Immunology · doi:10.3389/fimmu.2023.1259797 · Cited by 56 · see citing works
Hegedűs, C., Boros, G., Fidrus, E., Kis, G. N., Antal, M., Juhász, T., Janka, E. A., Jankó, L., Paragh, G., Emri, G., et al. (2019) · Cancers · doi:10.3390/cancers12010005 · Cited by 51 · see citing works
MicroRNAs Used in Combination with Anti-Cancer Treatments Can Enhance Therapy Efficacy
Mognato, M., & Celotti, L. (2015) · Mini-Reviews in Medicinal Chemistry · doi:10.2174/1389557515666150709115355 · Cited by 49 · see citing works
“The proteins of the NER/BER pathways seem to be connected to the DSB repair pathway; indeed ATM and ATR recruitment and their phosphorylation are negatively affected in cells defective in DDB2 or XPC functions, and DDB2 and XPC promote DNA repair through the BRCA1- and RAD51-dependent pathway [13].”
BackgroundInitiation of the ATM-Chk2 DNA damage response through the base excision repair pathway
Chou, W., Hu, L., Hsiung, C., & Shen, C. (2015) · Carcinogenesis · doi:10.1093/carcin/bgv079 · Cited by 43 · see citing works
Ray, A., Blevins, C., Wani, G., & Wani, A. A. (2016) · PLOS ONE · doi:10.1371/journal.pone.0159344 · Cited by 44 · see citing works
“Additionally, DDB2 and XPC regulate ATR and ATM recruitment and signaling following UVR exposures [41].”
BackgroundMethodInfluentialSelf-citationTiwari, M. K., Adaku, N., Peart, N. J., & Rogers, F. A. (2016) · Nucleic Acids Research · doi:10.1093/nar/gkw515 · Cited by 42 · see citing works
“This observation may be attributed to previous reports indicating that XPC is required for the recruitment of RAD51 to the damage site (38).”
ResultNucleotide excision repair leaves a mark on chromatin: DNA damage detection in nucleosomes
Apelt, K., Lans, H., Schärer, O. D., & Luijsterburg, M. S. (2021) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-021-03984-7 · Cited by 43 · see citing works
Loss of Genome Fidelity: Beta HPVs and the DNA Damage Response
Wendel, S. O., & Wallace, N. A. (2017) · Frontiers in Microbiology · doi:10.3389/fmicb.2017.02250 · Cited by 38 · see citing works
“ATM phosphorylates proteins critical for the FA, NER, and HR repair pathways (Ray et al., 2013, 2016; Shiloh and Ziv, 2013).”
BackgroundInherited Genetic Mutations and Polymorphisms in Malignant Mesothelioma: A Comprehensive Review
Panou, V., & Røe, O. D. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21124327 · Cited by 39 · see citing works
“XPC encodes an important protein for NER that responds to DNA damage induced by ultraviolet radiation by recruiting ATR and ATM kinases to the DNA defect sites [62].”
BackgroundLee, S.-A., Lee, D., Kang, M., Kim, S., Kwon, S.-J., Lee, H.-S., Seo, H.-R., Kaushal, P., Lee, N. S., Kim, H., et al. (2022) · Cell Death and Differentiation · doi:10.1038/s41418-022-01024-w · Cited by 40 · see citing works
XPC: Going where no DNA damage sensor has gone before
Nemzow, L., Lubin, A., Zhang, L., & Gong, F. (2015) · DNA repair · doi:10.1016/j.dnarep.2015.09.004 · Cited by 39 · see citing works
Roles of Ubiquitination and SUMOylation in DNA Damage Response
Su, S., Zhang, Y., & Liu, P. (2019) · Current Issues in Molecular Biology · doi:10.21775/cimb.035.059 · Cited by 34 · see citing works
Kemp, M. G., & Sancar, A. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.719740 · Cited by 33 · see citing works
Zhu, Q., Battu, A., Ray, A., Wani, G., Qian, J., He, J., Wang, Q., & Wani, A. A. (2015) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2015.01.005 · Cited by 33 · see citing works
Self-citationXPC beyond nucleotide excision repair and skin cancers
Zebian, A., Shaito, A. A., Mazurier, F., Rezvani, H. R., & Zibara, K. (2019) · Mutation Research/Reviews in Mutation Research · doi:10.1016/j.mrrev.2019.108286 · Cited by 34 · see citing works
Drissi, R., Chauvin, A., McKenna, A., et al. (2018) · Cell Cycle · doi:10.1080/15384101.2018.1553336 · Cited by 31 · see citing works
“Other repair mechanisms are also represented: CHD1 [48,49] or MUS81 [50] involved in the HR, DDB2 [51] in NER, or the CDK1 protein [52] which regulates NHEJ.”
BackgroundNucleotide excision repair efficiency in quiescent human fibroblasts is modulated by circadian clock
Bee, L., Marini, S., Pontarin, G., Ferraro, P., Costa, R., Albrecht, U., & Celotti, L. (2015) · Nucleic Acids Research · doi:10.1093/nar/gkv081 · Cited by 26 · see citing works
“The system can be broadly divided into two major sub pathways: the global genome NER (GG-NER), which is responsible for repairing lesions throughout the entire genome, and the transcriptioncoupled NER (TC-NER), which specifically repairs DNA lesions of active genes recognized by stalled RNA polymerase II (4,5).”
BackgroundATM and ATR Activation Through Crosstalk Between DNA Damage Response Pathways
Fedak, E. A., Adler, F. R., Abegglen, L. M., & Schiffman, J. D. (2021) · Bulletin of Mathematical Biology · doi:10.1007/s11538-021-00868-6 · Cited by 26 · see citing works
“Although ATM and ATR appear to compartmentalize two different classes of damage, researchers have discovered situations where ATMacts downstream ofATR,ATR acts downstream of ATM, and knocking down one of these kinases drastically changes the activity of the other (Hannan et al. 2002; Jazayeri et al. 2006; Cuadrado et…”
BackgroundMarchetti, A. L., Zhang, H., Kim, E. S., Yu, X., Jang, S., Wang, M., & Guo, H. (2021) · Journal of Virology · doi:10.1128/jvi.01360-21 · Cited by 26 · see citing works
“with this notion, DDB2 has been shown to recruit ATR kinase to the UV DNA damage sites for initiating DDR (60).”
BackgroundInfluentialEnhancement of UVB-induced DNA damage repair after a chronic low-dose UVB pre-stimulation
Drigeard Desgarnier, M.-C., & Rochette, P. J. (2018) · DNA Repair · doi:10.1016/j.dnarep.2018.01.008 · Cited by 24 · see citing works
Dong, H. F., Shi, Q., Song, X., Fu, J., Hu, L., Xu, D., Su, C., Xia, X., Song, E., & Song, Y. (2015) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2015.03.017 · Cited by 26 · see citing works
“This is in agreement with previous reports, which demonstrated that NER and NHEJ signalings regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites (Ray et al., 2013) maintaining a cross-talk with checkpoint proteins such as DNA-PKcs, Ku70, and Ku80 (Kim et al.”
ResultUV-induced G4 DNA structures recruit ZRF1 which prevents UV-induced senescence
Magis, A. D., Limmer, M., Mudiyam, V., Monchaud, D., Juranek, S., & Paeschke, K. (2023) · Nature Communications · doi:10.1038/s41467-023-42494-x · Cited by 23 · see citing works
“The CLR4-DDB2 complex is required for ef fi cient NER 57,58 .”
BackgroundMusich, P. R., Li, Z., & Zou, Y. (2017) · Advances in Experimental Medicine and Biology · doi:10.1007/978-3-319-56017-5_4 · Cited by 23 · see citing works
Circadian Rhythm of NER and ATR Pathways
Kang, T. (2021) · Biomolecules · doi:10.3390/biom11050715 · Cited by 24 · see citing works
“The lesion recognition factors in the GGR subpathway, XPE, and XPC alternatively can activate the ATR pathway by recruiting ATR kinase to the sites of UV damage [78].”
BackgroundXeroderma Pigmentosum Complementation Group C (XPC): Emerging Roles in Non-Dermatologic Malignancies
Nasrallah, N. A., Wiese, B. M., & Sears, C. R. (2022) · Frontiers in Oncology · doi:10.3389/fonc.2022.846965 · Cited by 21 · see citing works
“XPC, xeroderma pigmentosum group c; Ub, ubiquitin; SUMO, small ubiquitin-like modifier; P, phosphorylation site; DDB1, DNA damage-binding 1; DDB2, DNA damage binding 2; Cen2, centrin 2; HR23B, human UV excision repair protein RAD23; GG-NER, global genomic nucleotide excision repair; BER, base excision repair; MMR, mis…”
BackgroundInfluentialde Semir, D., Bezrookove, V., Nosrati, M., Dar, A. A., Miller, J. R., Leong, S. P. L., Kim, K. B., Liao, W. J., Soroceanu, L., McAllister, S. D., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-20-3450 · Cited by 21 · see citing works
Umar, S. A., Naikoo, S. H., Nazir, L. A., Tanveer, M. A., Divya, G., Archoo, S., Sharma, R. R., & Tasduq, S. A. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.726066 · Cited by 21 · see citing works
DDB2 regulates DNA replication through PCNA-independent degradation of CDT2
Wu, X., Yu, M., Zhang, Z., Leng, F., Ma, Y., Xie, N., & Lu, F. (2021) · Cell & Bioscience · doi:10.1186/s13578-021-00540-5 · Cited by 21 · see citing works
Budden, T., van der Westhuizen, A., & Bowden, N. A. (2018) · BMC Cancer · doi:10.1186/s12885-018-4010-9 · Cited by 17 · see citing works
“XPC and DDB2 are involved the activation of the checkpoint signalling protein ATR in response to UV-induced DNA damage [24].”
BackgroundSwope, V. B., Starner, R. J., Rauck, C., & Abdel‐Malek, Z. A. (2020) · Pigment Cell & Melanoma Research · doi:10.1111/pcmr.12823 · Cited by 18 · see citing works
Karbaschi, M., Macip, S., Mistry, V., Abbas, H. H. K., Delinasios, G. J., Evans, M. D., Young, A. R., & Cooke, M. S. (2015) · Toxicology Research · doi:10.1039/c4tx00197d · Cited by 18 · see citing works
Perucca, P., Mocchi, R., Guardamagna, I., Bassi, E., Sommatis, S., Nardò, T., Prosperi, E., Stivala, L. A., & Cazzalini, O. (2018) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2018.03.012 · Cited by 15 · see citing works
Flori, E., Mastrofrancesco, A., Kovacs, D., Bellei, B., Briganti, S., Maresca, V., Cardinali, G., & Picardo, M. (2017) · Scientific Reports · doi:10.1038/s41598-017-09578-3 · Cited by 16 · see citing works
Dissociation Dynamics of XPC-RAD23B from Damaged DNA Is a Determining Factor of NER Efficiency
Hilton, B., Sathyaraj, G., Xu, L., Mazumder, S., Musich, P. R., Cho, B. P., & Zou, Y. (2016) · PLoS ONE · doi:10.1371/journal.pone.0157784 · Cited by 13 · see citing works
Prognostic Significance of Nuclear Phospho-ATM Expression in Melanoma
Bhandaru, M., Martinka, M., McElwee, K. J., & Rotte, A. (2015) · PLoS ONE · doi:10.1371/journal.pone.0134678 · Cited by 13 · see citing works
Düzenli, U., Altun, Z. S., Olgun, Y., Aktaş, S., Pamukoğlu, A., Çetinayak, O., Bayrak, A. F., & Olgun, L. (2018) · International Journal of Radiation Biology · doi:10.1080/09553002.2019.1547847 · Cited by 13 · see citing works
“Xpc helps ATM and ATR to accumulate in damage sites caused by radiation and therefore has indirect functions in double-strand repair (Ray et al. 2013).”
BackgroundA protein with broad functions: damage-specific DNA-binding protein 2
Bao, N., Han, J., & Zhou, H. (2022) · Molecular Biology Reports · doi:10.1007/s11033-022-07963-4 · Cited by 13 · see citing works
“GG-NER repairs DNA damage both in transcribed and non-transcribed DNA strands.”
BackgroundInfluentialThe impact of ionizing radiation on placental trophoblasts
Kanter, D. J., O'Brien, M. B., Shi, X., et al. (2014) · Placenta · doi:10.1016/j.placenta.2013.12.011 · Cited by 13 · see citing works
“DDB2, a damage-related protein and part of a heterodimeric complex that participates in nucleotide excision repair, is increased in irradiated human fibroblasts [41].”
BackgroundMisra, S., Zhang, X., Wani, N. A., Sizemore, S. T., & Ray, A. (2020) · Oncotarget · doi:10.18632/oncotarget.27485 · Cited by 13 · see citing works
“Immunoblotting was performed as described in [42, 43].”
Self-citationJianhong, Q., Wang, X., Meng, X., Zheng, Y., Li, G., Ma, J., Ye, G., Li, Y., & Li, J. (2014) · PLoS ONE · doi:10.1371/journal.pone.0115224 · Cited by 12 · see citing works
Chromatin association of XRCC5/6 in the absence of DNA damage depends on the XPE gene product DDB2
Fantini, D., Huang, S., Asara, J. M., et al. (2016) · Molecular Biology of the Cell · doi:10.1091/mbc.e16-08-0573 · Cited by 12 · see citing works
“DDB2 was shown to be involved in the activation of ATM/ATR after UV irradiation (Ray et al., 2013).”
BackgroundThe XPA Protein—Life under Precise Control
Krasikova, Y. S., Lavrik, O. I., & Rechkunova, N. I. (2022) · Cells · doi:10.3390/cells11233723 · Cited by 12 · see citing works
Hutcherson, R. J., & Kemp, M. G. (2019) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/j.mrfmmm.2019.111678 · Cited by 9 · see citing works
Formaldehyde inhibits UV-induced phosphorylation of histone H2AX
Yang, G., Komaki, Y., Yoshida, I., & Ibuki, Y. (2019) · Toxicology in Vitro · doi:10.1016/j.tiv.2019.104687 · Cited by 10 · see citing works
DNA damage mediated by UV radiation and relative repair mechanisms in mammals
Wang, Y., Deng, X., & Zhou, M. (2022) · Genome Instability & Disease · doi:10.1007/s42764-022-00090-1 · Cited by 13 · see citing works
“The core NER protein XPC or DDB2 deletion reduced the phosphorylation of ATM and ATR (Ray et al., 2013).”
BackgroundInfluentialLu, J., Das, M., Kanji, S., Aggarwal, R., Joseph, M., Ray, A., Shapiro, C. L., Pompili, V. J., & Das, H. (2014) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2014.04.003 · Cited by 10 · see citing works
“Transfection with various RNAs in A2780 cells were conducted using LipofectamineTM 2000 transfection reagents (Invitrogen) according to the manufacturer’s instruction and earliser published methods [23].”
MethodSelf-citationYun, K., & Wang, Z. Y. (2017) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2017.05.001 · Cited by 8 · see citing works
Prósz, A. G., Sahgal, P., Huffman, B. M., Sztupinszki, Z. M., Morris, C. X., Chen, D. J., Börcsök, J., Dióssy, M., Tisza, V., Spisák, S., et al. (2024) · npj Precision Oncology · doi:10.1038/s41698-024-00561-6 · Cited by 9 · see citing works
“To con fi rm these results, we performed a second proteo-probe assay involving damaged-DNA binding protein 2 (DDB2), an essential initiation factor with preferential activity in GGR NER pathway 38 that binds to UV-induced 6,4-photoproduct.”
MethodSharin, T., Gyasi, H., Jones, S. P., et al. (2021) · Environmental and Molecular Mutagenesis · doi:10.1002/em.22433 · Cited by 7 · see citing works
Bérešová, L., Veselá, E., Chamrád, I., Voller, J., Yamada, M., Fürst, T., Lenobel, R., Chromá, K., Gurský, J., Křížová, K., et al. (2016) · Journal of Proteome Research · doi:10.1021/acs.jproteome.6b00622 · Cited by 4 · see citing works
Splicing DNA Damage Adaptations for the Management of Cancer Cells
Singh, A. K., Yadav, D., & Malviya, R. (2023) · Current Gene Therapy · doi:10.2174/0115665232258528231018113410 · Cited by 4 · see citing works
Lee, J.-M., Park, J.-M., & Kang, T.-H. (2016) · BMB Reports · doi:10.5483/bmbrep.2016.49.10.097 · Cited by 3 · see citing works
Mavroeidi, D., Papanikolaou, C. A., Deligianni, E., Malamos, P., Stamou, P., Syrigos, K. N., & Souliotis, V. L. (2026) · Cancers · doi:10.3390/cancers18050820 · Cited by 5 · see citing works
“NER sensors such as DDB2 and XPC can recruit ATR/ATM to UV-induced lesions, where ATR subsequently phosphorylates factors like XPA to stabilize and enhance NER activity, particularly in G1 phase [48].”
Characterization of the multifunctional XPG protein during Nucleotide-excision-repair
Schubert, S. (2014) · doi:10.53846/goediss-4515 · Cited by 2 · see citing works
DDB2 Regulates DNA Replication through PCNA-Independent Degradation of CDT2Preprint
Wu, X., Yu, M., Zhang, Z., et al. (2020) · Research Square · doi:10.21203/rs.3.rs-93459/v1 · Cited by 1 · see citing works
Fu, Y., Jiang, C., Chen, Y., Li, F., He, X., Ma, L., Xie, S., Ye, L., Ge, S., Yu, J., et al. (2026) · Cancer Letters · doi:10.1016/j.canlet.2026.218322 · Cited by 1 · see citing works
Dynamics of the p53 response to ionizing and ultraviolet radiationPreprint
Fedak, E. A., Adler, F. R., Young, E. L., Abegglen, L. M., & Schiffman, J. D. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/367995 · Cited by 1 · see citing works
“Fibroblast data suggest that CPDs are initially repaired quickly, but that after the 150 percentage of CPDs remaining in the cell after 8 hours is much higher than we would 151 predict from an exponential model with a constant repair rate [30].”
BackgroundRAD9A Stabilization and Destabilization Processes in Checkpoint Maintenance and Checkpoint Recovery
Zambrano, O., & Frend, W. H. C. (2015) · QSpace (Queen's University Library)
Lofrano, A., Wruck, W., Graffmann, N., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2025.12.02.691678
“To determine whether BPDE activates the nucleotide excision repair (NER) pathway, we analyzed the transcriptional response of two key lesion-recognition factors [71]: Xeroderma Pigmentosum Group C (XPC) and DNA Damage-Binding Protein 2 (DDB2).”
de Semir, D., Bezrookove, V., Nosrati, M., Dar, A. A., Miller, J. R., Leong, S. P. L., Kim, K. B., Liao, W. J., Soroceanu, L., McAllister, S. D., et al. (2023) · doi:10.1158/0008-5472.c.6513430.v1
What p53 sees: ATM and ATR activation through crosstalk between DNA damage response pathwaysPreprint
Fedak, E. A., Adler, F. R., Abegglen, L. M., et al. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.04.237131
Beardmore, R. (2015) · Bangor University Research Portal (Bangor University)
Black, J. A., Crouch, K., Lemgruber, L., Lapsley, C. T., Dickens, N. J., Mottram, J. C., & McCulloch, R. (2018) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/435198
Cai, Q. (2014) · eScholarship (California Digital Library)
Api5 Regulates Genomic Stability and Chemotherapy Resistance in CancerPreprint
Abraham, B., Upadhyay, A., Malhotra, K., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.06.23.734059
“The DDB1-DDB2 complex detects distortions caused by cross-linked nucleotides and initiates the sequential recruitment of NER proteins, including XPC, XPB, XPD, XPA, and XPG, to the damaged sites (Ray et al., 2013).”
Diagnostic tool to identify and treat DNA repair deficient gastroesophageal adenocarcinomasPreprint
Prósz, A. G., Sahgal, P., Morris, C. X., et al. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.07.14.500118
Murba, A. A., Ibrahim, M. A., Zakaria, S. S., Adenan, N. H., Jamaludin, M. I., Nishitani, H., Ali, M. S. M., & Mazian, M. A. (2026) · Asia-Pacific Journal of Molecular Biology and Biotechnology · doi:10.35118/apjmbb.2026.034.1.01
Umar, S. A., & Tasduq, S. A. (2020) · bioRxiv · doi:10.1101/2020.09.28.316273
“Damage related protein DDB2 have been shown to facilitate the recruitment of ATM and ATR to sites of DNA damage and promote the activation of cell cycle arrest pathways [39-41].”
BackgroundHamed, H. A. (2018) · ORCA Online Research @Cardiff (Cardiff University)
Xu, Y.-J., Gao, A., Dev, K., Zheng, Y., Alyahya, M. Y., Pasam, S., Kaur, G., & Zhou, C. (2026) · PLoS Genetics · doi:10.1371/journal.pgen.1012052
“Consistent with this notion, several DNA repair proteins have been reported in other model systems to facilitate the recruitment of the checkpoint sensor proteins to the damage sites for checkpoint initiation [50–53].”
- Authors
- Ray, A., Milum, K., Battu, A., Wani, G., & Wani, A. A.
- Affiliations
- The Ohio State University (US)
- The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (US)
- Corresponding author
- Ray, Alo
- Wani, Altaf A.
- ORCID
- Venue
- DNA Repair
- Publisher
- Elsevier BV
- Published
- 2013-04
- Volume
- 12
- Issue
- 4
- Pages
- 273-283
- ISSN
- 1568-7856 (ISSN-L)
- 1568-7864
- PMC
- PMC4174315
- OpenAlex
- W1996571302
- Cited by
- 85
- References
- 72
- Citations by year
- 2026: 5 · 2025: 1 · 2024: 1 · 2023: 5 · 2022: 7 · 2021: 9 · 2020: 3 · 2019: 8 · 2018: 11 · 2017: 5 · 2016: 11 · 2015: 10 · 2014: 9
- FWCI
- 4.48
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- DNA repair (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- the National Institute of Health (ES2388, ES12991, CA93413)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- nucleotide excision repair, DDB2, XPC, ATR kinase, ATM kinase, DNA damage checkpoint, Chk1, Chk2, H2AX, BRCA1, RAD51, DNA damage recognition, checkpoint signaling
- MeSH terms
- Checkpoint Kinase 1, DNA Damage, DNA Repair, DNA-Binding Proteins, HeLa Cells, Histones, Humans, Mutation, Phosphorylation, Protein Binding, Protein Kinases, Ultraviolet Rays, Protein Serine-Threonine Kinases, Cell Cycle Proteins, BRCA1 Protein, Protein Transport, Tumor Suppressor Proteins, RNA, Small Interfering, Rad51 Recombinase, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Claims read by deepseek-v4.1-flash under definition version 3 (extract-v3) on 2026-10-06.
Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-06.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
