The DOI matches its Crossref record; 151 of the 151 references it cites were found in a registry or an index; none of the 119 sources its claims cite is checked for support yet.
Cell cycle checkpoint signaling through the ATM and ATR kinases
Open accessAbstract
The genomes of eukaryotic cells are under continuous assault by environmental agents (e.g., UV light and reactive chemicals) as well as the byproducts of normal intracellular metabolism (e.g., reactive oxygen intermediates and inaccurately replicated DNA).Whatever the origin, genetic damage threatens cell survival, and, in metazoans, leads to organ failure, immunodeficiency, cancer, and other pathologic sequelae.
Overview
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Written from the paper’s full text.
TL;DR
This review synthesizes the roles of ATM and ATR, two phosphoinositide 3-kinase-related kinases, in DNA damage and cell-cycle checkpoint signaling. It argues that ATM primarily handles ionizing radiation-induced double-strand breaks, while ATR is more central to replication stress, UV damage, and S/G2 checkpoint responses.
Key findings
- ATM and ATR are S/T-Q-directed protein kinases; ATM activity increases several-fold within 1 h after ionizing radiation or radiomimetic treatment, whereas ATR did not show such activation in immune-complex assays but redistributes into nuclear foci after DNA damage.
- ATM and ATR phosphorylate overlapping substrates, including p53 at Ser15, MDM2 at Ser395, Chk2 at Thr68, p53 at Ser20 via Chk2, Cdc25A at Ser123 via Chk2, NBS1 at Ser343/Ser397/Ser615, and BRCA1 within its SQ cluster domain, which contains 14 S-Q motifs, 10 in an ~300-amino-acid region (residues 1250–1550), with major IR-induced sites at Ser1387, Ser1423, and Ser1524.
- In S phase, the ATM-Chk2-Cdc25A pathway suppresses radioresistant DNA synthesis; ATR is proposed to govern a parallel replication-stress pathway, and ATR phosphorylates six Ser/Thr residues in the BRCA1 carboxyl terminus.
- In G2, ATR-Chk1 signaling is implicated when damage occurs before S phase completion, while ATM is required when damage occurs during G2 itself; Chk1−/− embryonic stem cells show reduced G2 arrest after IR, and Chk2−/− cells show a maintenance defect.
- Extranuclear ATM is linked to insulin/IGF signaling, including phosphorylation of PHAS-I/4E-BP1 at Ser111 and regulation of IGF-1 receptor expression.
Methods
- Narrative review, not a primary experimental study; it synthesizes published literature on mammalian ATM and ATR checkpoint signaling, with brief references to yeast and Xenopus model systems.
- Evidence base consists of cited studies; the article cites 145 references, 77 of which are noted as freely accessible.
- Main analysis is conceptual and mechanistic, organized around PIKK family structure, ATM/ATR biochemistry, associated complexes such as BASC, G1/S/G2 checkpoint functions, extranuclear ATM roles, and therapeutic implications.
Limitations
- The paper states that understanding of DNA damage sensors and the mechanisms that initiate and terminate checkpoint activation remains skeletal; DNA-dependent activation of ATM/ATR is controversial, with opposite results across laboratories; ATR activation was not detected in whole-cell extracts; and definitive tests await an ATR-deficient cell line with an intact G1 checkpoint.
- Evident from the text: this is a review without systematic search or new data, many conclusions rest on in vitro immune-complex kinase assays with millimolar Mn2+ and detergent-sensitive ATM activity, and some cited findings are in press or unpublished; proposed therapeutic uses of ATM/ATR inhibitors are speculative.
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Claims the paper makes
73 Not checked yet · 22 Own interpretation · 16 No basis given · 4 Own result
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Under identical experimental conditions, ATM did not enter into nuclear foci in cells damaged with IR or other DNA-damaging agents.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
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In the paper
“A peptide containing these sites was phosphorylated at a higher rate by ATR than by ATM (Kim et al. 1999), and we have found that a GST-hRad17 fusion protein is a significantly better substrate for ATR than for ATM (Bao et al. 2001; R.S. Tibbetts and R.T. Abraham, unpubl.).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
What the sources say
- Not checked yetcites Bao et al. 2001
- Not checked yetcites R.S. Tibbetts and R.T. Abraham, unpubl.
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In the paper
“On the other hand, our group has failed to detect any increases in the in vitro kinase activity of ATR after treatment of cells with various genotoxic agents, including IR and UV light (R.S. Tibbetts and R.T. Abraham, unpubl.).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
What the sources say
- Not checked yetcites R.S. Tibbetts and R.T. Abraham, unpubl.
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In the paper
“Disruption of this pathway yields the radioresistant DNA synthesis (RDS) phenotype.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
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In the paper
“The amino-terminal cross-hatched box indicates a functionally undefined region of homology between ATM (residues 1493-1773) and ATR (residues 1191-1463).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
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In the paper
“No significant homology was detected between the predicted FATC domains of these two proteins.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
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In the paper
“Hence, loss of either of two biochemically connected checkpoint kinases, ATM or Chk2, paradoxically increases the resistance of immature (CD4 + CD8 + ) T cells to ionizing radiation (IR)-induced apoptosis (Xu and Baltimore 1996;Hirao et al. 2000).”
What the sources say
- Not checked yetcites Xu and Baltimore 1996
- Not checked yetcites Hirao et al. 2000
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In the paper
“The catalytic domains (∼300 amino acids) of the PIKK family members are located near their carboxyl termini, and are flanked by two loosely conserved domains termed FAT (FRAP/ATM/TRRAP) and FATC (the “C” indicates carboxy-terminal) (Bosotti et al. 2000).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The PIKK family
What the sources say
- Not checked yetcites Bosotti et al. 2000
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In the paper
“First, the protein kinase activity of ATM, but not of ATR or DNA-PK, is quite sensitive to inhibition by the nonionic detergents (e.g., Triton X-100, NP-40) commonly used to prepare whole cell or nuclear extracts (Gottlieb and Jackson 1993;Sarkaria et al. 1998Sarkaria et al. , 1999;;Yavuzer et al. 1998).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
What the sources say
- Not checked yetcites Gottlieb and Jackson 1993
- Not checked yetcites Sarkaria et al. 1998
- Not checked yetcites Yavuzer et al. 1998
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, all of the PIKKs characterized to date, mammalian or otherwise, function as S/T-Q-directed kinases, with the no-table exception of the yeast and mammalian TOR proteins.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
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- It may state two separate claims as one. 33
- Probably not a substantial claim. 1
A result the paper reports from its own data — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Our own results indicate that hSMG1 is found in both the nucleus and cytoplasm, and, like ATM and ATR, exhibits phosphotransferase activity toward a variety of proteins containing Ser-Gln motifs under in vitro assay conditions.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The PIKK family
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In the paper
“However, members of the Rad group of checkpoint proteins, which include Rad17, Rad1, Rad9, Rad26, and Hus1 (nomenclature based on the Schizosaccharomyces pombe gene products) are widely expressed in all eukaryotic cells, and are prime suspects in the lineup of candidate DNA damage sensors (Green et al. 2000;O'Connell et al. 2000).”
What the sources say
- Not checked yetcites Green et al. 2000
- Not checked yetcites O'Connell et al. 2000
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In the paper
“On the other hand, mTOR plays no identifiable role in genome surveillance; rather, this PIKK coordinates G 1 phase progression with the supply of nutrients and growth factors (Gingras et al. 2001).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The PIKK family
What the sources say
- Not checked yetcites Gingras et al. 2001
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In the paper
“The catalytic subunit of DNA-dependent protein kinase (DNA-PK cs ) functions as a heterotrimeric complex containing two Ku subunits (Ku-70 and Ku-80), and makes its own crucial contribution to genome maintenance by overseeing the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (dsb) repair (Smith and Jackson 1999).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The PIKK family
What the sources say
- Not checked yetcites Smith and Jackson 1999
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In the paper
“Interestingly, yet another member of the Rad family, Rad17, bears homology to the RFC subunits and, in fact, associates with RFC subunits to form a putative checkpoint clamp loading complex (CLC) that governs the interaction of the Rad1-Rad9-Hus1 CSC with damaged DNA (Green et al. 2000;O'Connell et al. 2000).”
What the sources say
- Not checked yetcites Green et al. 2000
- Not checked yetcites O'Connell et al. 2000
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In the paper
“Three of these Rad proteins, Rad1, Rad9, and Hus1, exhibit structural similarity to the proliferating cell nuclear antigen (PCNA), and accumulating evidence supports the idea that this similarity may extend to function as well (Thelen et al. 1999;Burtelow et al. 2000).”
What the sources say
- Not checked yetcites Thelen et al. 1999
- Not checked yetcites Burtelow et al. 2000
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“Immune complex kinase assays quickly revealed that, like DNA-PK, ATM and ATR displayed S/T-Q-directed kinase activities under in vitro conditions, and that a physiologically relevant substrate for both protein kinases was p53 (Banin et al. 1998;Canman et al. 1998;Tibbetts et al. 1999;Ziv et al. 2000).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
What the sources say
- Not checked yetcites Banin et al. 1998
- Not checked yetcites Canman et al. 1998
- Not checked yetcites Tibbetts et al. 1999
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“Collectively, these results hint that ATM and ATR respond to DNA damage in fundamentally different fashions: One checkpoint kinase (ATM) becomes catalytically active, whereas the other (ATR) redistributes into DNA damage-induced nuclear foci, where it presumably gains access to its substrates.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
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In the paper
“These efforts identified a consensus phosphorylation site [(M/F)-(Q/P)-L-S-Q-(E/Q)] that was in reasonable agreement with that defined by Kastan and coworkers (Kim et al. 1999).Remarkably, the relatively unbiased peptide selection strategy zeroed in on a core L-S-Q-E target sequence, which was identical to that surrounding the Ser 15 site in p53.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Biochemistry of the ATM and ATR kinases
What the sources say
- Not checked yetcites O'Neill et al. 2000
- Not checked yetcites Kim et al. 1999
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In the paper
“The latter complex plays impor-tant roles in the recombinational repair of DNA dsbs, and the loss of one of the components of this complex, NBS1, gives rise to the Nijmegen breakage syndrome, a chromosomal instability disorder that bears several similarities to A-T (Shiloh 1997).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The ATM/ATR-associated signaling machinery: complex complexes
What the sources say
- Not checked yetcites Shiloh 1997
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In the paper
“Many of these foci react with both ATR-and BRCA1-specific antibodies, suggesting that the two proteins colocalize at sites of DNA damage.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The ATM/ATR-associated signaling machinery: complex complexes
What the sources say
- Not checked yetcites Scully et al. 1997
- Not checked yetcites Tibbetts et al. 2000
hedgedcorrelational- Asserted: passes — The authors put it forward as true.
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In the paper
“The breast cancer susceptibility protein, BRCA1, is a critical component of the checkpoint signaling and DNA repair machinery, and is a direct target for phosphorylation by ATM and ATR in cells exposed to genotoxic stress (Cortez et al. 1999;Scully and Livingston 2000;Scully et al. 2000;Tibbetts et al. 2000).”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The ATM/ATR-associated signaling machinery: complex complexes
What the sources say
- Not checked yetcites Cortez et al. 1999
- Not checked yetcites Scully and Livingston 2000
- Not checked yetcites Tibbetts et al. 2000
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In the paper
“In cells rendered functionally deficient for ATR by overexpression of a kinase-inactive ATR KI mutant (Cliby et al. 1998), the early phase (0-2 h) of IR-induced p53 phosphorylation was not impaired, which is consistent with the idea that ATM serves as the major Ser 15 kinase during the acute response to IR”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
What the sources say
- Not checked yetcites Tibbetts et al. 1999
hedged- Asserted: passes — The authors put it forward as true.
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In the paper
“Moreover, phosphorylation of Ser 15 was rapidly induced in IR-treated cells, and this response was ATM dependent, as IR-induced Ser 15 phosphorylation was significantly, but not completely, suppressed in A-T cells”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
What the sources say
- Not checked yetcites Siliciano et al. 1997
- Not checked yetcites Banin et al. 1998
- Not checked yetcites Canman et al. 1998
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In the paper
“However, the ATR KI -overexpressing cells did show a significant defect in their ability to maintain phosphorylation of Ser 15 at later times, which suggests that the maintenance phase of p53 phosphorylation was more highly dependent on ATR.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
What the sources say
- Not checked yetcites Tibbetts et al. 1999
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“On the other hand, treatment of human fibroblasts with UV light triggered a Ser 15 phosphorylation response that was largely independent of ATM expression, and was strongly reduced, at all times postirradiation, by overexpression of ATR KI”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
What the sources say
- Not checked yetcites Tibbetts et al. 1999
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In the paper
“It turns out, however, that Ser 15 phosphorylation is not sufficient to disrupt the p53-MDM2 interaction; rather, this modification stimulates the transactivating function of p53 by enhancing the binding of this protein to the transcriptional coactivator, p300”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
What the sources say
- Not checked yetcites Dumaz and Meek 1999
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“In the absence of ATM, or in normal cells that incur a high level of IR-induced DNA damage, ATR serves mainly as a backup kinase for ATM.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Unlike the Ser 15 modification mentioned earlier, phosphorylation at Ser 20 interferes directly with the binding of p53 to MDM2, thereby favoring p53 accumulation in response to IR-induced DNA damage.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
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In the paper
“In the absence of ATM, the IR-induced decrease in DNA synthesis is dampened significantly, giving rise to the RDS phenotype.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Painter and Young 1980
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In the paper
“Remarkably, mutant hChk2 alleles associated with a variant form of Li-Fraumeni syndrome (Bell et al. 1999) failed to bind and/or phosphorylate Cdc25A (Falck et al. 2001), which implies that genetic lesions in the RDS pathway promote genome instability and cancer development.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Falck et al. 2001
- Not checked yetcites Bell et al. 1999
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The results obtained by Falck et al. (2001) show that hChk2 phosphorylates Ser 123 in Cdc25A, and that this modification targets Cdc25A for ubiquitin-dependent degradation.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Falck et al. 2001
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“The appearance of these foci is dependent on the expression of NBS1; however, the absence of major DNA repair defects in cells from NBS patients indicates that the Mre11-Rad50 complex carries out its repair functions quite capably in NBS1-deficient cells”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Petrini 1999
hedgeddirect- Asserted: passes — The authors put it forward as true.
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In the paper
“ATM phosphorylates NBS1 on up to three serine residues (Ser 343, Ser 397, and Ser 615), and that Ser → Ala substitutions at any one of these sites generated a mutant NBS1 protein that failed to complement the checkpoint defects in NBS cells”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Gatei et al. 2000b
- Not checked yetcites Lim et al. 2000
- Not checked yetcites Wu et al. 2000
plaindirect- Asserted: passes — The authors put it forward as true.
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In the paper
“Treatment of cells with IR induces the rapid formation of nuclear foci containing the NBS1-Mre11-Rad50 complex, and a technologically elegant study offered strong evidence that the foci assemble in close proximity to DNA dsbs”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Nelms et al. 1998
boosteddirect- Asserted: passes — The authors put it forward as true.
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A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“With the caveat in mind that overexpressed ATR KI may nonspecifically cross-inhibit ATM function, these results suggest either that ATR also resides upstream of hChk2, or that ATR regulates a parallel pathway that contributes to the suppression of DNA synthesis in IR-damaged cells.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
hedgedconditional- Asserted: passes — The authors put it forward as true.
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In the paper
“Interestingly, NBS cells also display the RDS phenotype, which suggests that the NBS1 protein is an upstream regulator of Cdc25A stability in IR-treated cells.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
hedgedconditional- Asserted: passes — The authors put it forward as true.
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It may state two separate claims as one.
In the paper
“Cortez et al. (1999) observed that the phosphorylation of BRCA1 in IR-damaged cells was significantly impaired in the absence of ATM, and demonstrated that at least five of the predicted S-Q target sites in the SCD were phosphorylated by ATM in vitro.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Cortez et al. 1999
boosteddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
In the paper
“The carboxy-terminal region of BRCA1 contains numerous S-Q motifs (total of 14), and, of these potential ATM/ATR target sequences, 10 are localized in an ∼300 amino acid stretch (residues 1250-1550) termed the SQ cluster domain (SCD)”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The S-phase checkpoint
What the sources say
- Not checked yetcites Cortez et al. 1999
plain- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: unclear — It is unclear whether the paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“In contrast to ATR, ATM seems dedicated to providing the cell with a rapid protective response to an extremely lethal form of DNA damage, the DNA dsb.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
hedgeddirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“it is likely that, outside of the laboratory setting, the intrinsic accoutrements of life as a multicellular organism, such as continuous assaults by oxygen-derived radicals, and the need to generate a diverse repertoire of antigen-responsive lymphocytes, generated evolutionary pressure for the development of a checkpoint signaling module geared toward sounding the DNA dsb alarm at the first sign”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: fails — It may be too vague to check against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: fails — The paper may give no reason why it holds.
Probably not a substantial claim. It may be too vague to check against evidence. The paper may give no reason why it holds.
A conclusion the paper draws from its own results — it cites no other source for it, so there is none to check. The quote shows it is in the paper.
In the paper
“The pathway is governed primarily by ATR, and may use members of the Rad family of checkpoint proteins as damage sensors and as scaffolds for the assembly of checkpoint signaling complexes.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
hedgedconditional- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“The checkpoint response leads to the proteosome-mediated degradation of Cdc25A, and, in turn, the failure to maintain activation of cyclin•cdk2 complexes and a resultant inhibition of DNA synthesis.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper states this without a source or data behind it here, so there is nothing to check it against. The quote shows it is in the paper.
In the paper
“Both branches converge on the Cdc25C phosphatase, and prevent activation of the mitotic cyclin B•cdc2 complex by inducing the cytoplasmic sequestration and/or catalytic inhibition of Cdc25C.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > Conclusions
plaindirect- Asserted: passes — The authors put it forward as true.
- Checkable: passes — It can be checked against evidence.
- Load-bearing: passes — The paper’s conclusions depend on it.
- Based: passes — The paper gives a reason why it holds.
It may state two separate claims as one.
The paper relies on this without support.
Cell-cycle checkpoints detect damaged or abnormally structured DNA and coordinate cell-cycle progression with DNA repair.
“The overall function of these checkpoints is to detect damaged or abnormally structured DNA, and to coordinate cell-cycle progression with DNA repair.”
The paper relies on this without support.
In mammalian cells, ATM and ATR play critical roles in early signal transmission through cell-cycle checkpoints.
“In mammalian cells, two PIKK family members, ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad 3-related), play critical roles in early signal transmission through cellcycle checkpoints.”
The paper relies on this without support.
The catalytic domains of PIKK family members transfer phosphate exclusively to protein rather than lipid substrates.
“Despite the sequence similarity to phosphoinositide kinases, the catalytic domains of the PIKKs appear to transfer phosphate exclusively to protein rather than lipid substrates.”
The paper relies on this without support.
ATM-deficient cells display significant defects in the G1, S, and G2 checkpoints.
“Before the cloning of the ATM gene, the dedicated efforts ATM/ATR kinases and checkpoint signaling of many laboratories documented that ATM-deficient cells displayed significant defects in the G 1 , S, and G 2 checkpoints.”
The paper relies on this without support.
Rad1, Rad9, and Hus1 form a heterotrimeric complex in intact cells.
“Rad1, Rad9, and Hus1 are also found as a heterotrimeric complex in intact cells, and it has been postulated that the Rad1-Rad9-Hus1 complex encircles DNA at or near sites of damage to form a checkpoint sliding clamp (CSC) (O'Connell et al. 2000), which could serve as a nucleus for the recruitment of the checkpoint signaling machinery to broken or abnormally structured DNA.”
The paper relies on this without support.
Most or all forms of genotoxic stress rapidly increase p53 levels primarily by increasing p53 protein stability.
“DNA damage induced by most, if not all, forms of genotoxic stress induces a rapid increase in the level of p53, a response that is mediated primarily through an increase in protein stability.”
The paper relies on this without support.
Genotoxic stress induces posttranslational modifications that regulate p53 transcriptional activation.
“In addition to triggering the accumulation of p53, genotoxic stress induces posttranslational modifications that regulate the transcriptional activating functions of this protein.”
The paper relies on this without support.
p21 is a key transcriptional target of p53 for the G1 checkpoint.
“With respect to the G 1 checkpoint, a key target for transcriptional activation by p53 is the cyclin-dependent kinase inhibitor, p21 (also termed WAF1 or CIP1).”
The paper relies on this without support.
The p53-dependent increase in p21 suppresses cyclin E- and cyclin A-associated cdk2 activities, preventing G1-to-S progression.
“The p53-dependent increase in p21 expression suppresses cyclin Eand cyclin A-associated cdk2 activities, and thereby prevents G 1 -to-S phase progression.”
The paper relies on this without support.
Nonhomologous repair mechanisms are inherently less precise and increase the risk that inaccurately repaired DNA is carried into M phase.
“Nonhomologous repair mechanisms also play very prominent roles in DNA dsb repair during all phases of the cell cycle; however, these mechanisms are inherently less precise, and therefore confer an increased risk that inaccurately repaired DNA will be carried forward into M phase.”
The paper relies on this without support.
A main route by which tumor cells become genetically unstable is mutation that impairs or removes cell-cycle checkpoints.
“A major mechanism whereby tumor cells acquire genetic instability is through the acquisition of mutations that weaken or eliminate cell-cycle checkpoints.”
The paper relies on this without support.
Checkpoint control loss occurs especially often as cancer advances.
“Loss of checkpoint controls is particularly prevalent in the later stages of cancer development, and it is these tumor cells that tend to be especially refractory to killing by conventional anticancer agents, many of which either damage DNA directly or interfere with DNA replication.”
The paper relies on this without support.
Such checkpoint-deficient tumor cells are often hard to kill with standard anticancer drugs that damage DNA or block replication.
“Loss of checkpoint controls is particularly prevalent in the later stages of cancer development, and it is these tumor cells that tend to be especially refractory to killing by conventional anticancer agents, many of which either damage DNA directly or interfere with DNA replication.”
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?
The source backs part of the claim, not all of it — or backs it for a different population, condition or comparison.
In the citing paper
“ATM kinase seems to be activated primarily in response to the induction of double-strand breaks whereas ATR is critical for cellular checkpoint responses to stalled replication forks and to many types of DNA damage, such as those induced by UV light and cisplatin (16,17).”
From Phosphorylation of Nucleotide Excision Repair Factor Xeroderma Pigmentosum Group A by Ataxia Telangiectasia Mutated and Rad3-Related–Dependent Checkpoint Pathway Promotes Cell Survival in Response to UV Irradiation (2006) · cites this paper as [16]
Experimental — accuracy not yet measuredThe cited source says what the claim attributes to it.
In the citing paper
“By coordinating cell cycle progression with DNA repair, cell cycle checkpoints help maintain genetic stability and prevent carcinogenesis (Abraham, 2001).”
From ATR–Chk1 Pathway Inhibition Promotes Apoptosis after UV Treatment in Primary Human Keratinocytes: Potential Basis for the UV Protective Effects of Caffeine (2009) · cites this paper as Abraham, 2001
In the citing paper
“In A-T cells that completely lack ATM activity, the damage response pathways eventually get activated because of the action of other kinases, such as ATR, which belongs to the same protein family as ATM (Abraham, 2001;Shiloh, 2001;Shiloh and Kastan, 2001).”
From Requirement of the MRN complex for ATM activation by DNA damage (2003) · cites this paper as Abraham, 2001
In the citing paper
“Phosphorylation activates these downstream proteins resulting in arrest of cell cycle progression, activation of DNA repair and, in cases of severe damage, apoptotic cell death 22, 34, 35.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [22]
In the citing paper
“Although it functions in multiple DDR processes 21 ATR is the primary regulator of the nucleotide excision repair pathway due to its ability to detect the replicative and transcriptional stresses caused by UV-induced damage and other bulky DNA adducts resulting from chemical toxins and some chemotherapeutic agents 22–25.”
From Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation (2017) · cites this paper as [22]
In the citing paper
“According to the prevailing model, 56 DNA damage-induced G2 arrest is triggered by the ATM/ATR-activated checkpoint kinases Chk1/2 that inhibit Cdc25 phosphatases, which are activators of the key mitotic regulator, cyclin B1-Cdk1 (Fig. 2).”
From Senescence from G2 arrest, revisited (2015) · cites this paper as [56]
In the citing paper
“ATM specifically phosphorylates SQ/TQ motifs”
From USP10 Regulates p53 Localization and Stability by Deubiquitinating p53 (2010) · cites this paper as Abraham, 2001
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
Each contradiction between two passages listed here was confirmed by an independent check.
Rated minor: it would not touch a result — a value no result rests on, a p-value that stays on the same side of the significance level, or a conflict that is clerical, resolved elsewhere in the paper, or outside its own findings.
In the paper
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > The G 1 checkpoint
“Indeed, Dumaz et al. (1999) have shown that Ser 15 phosphorylation greatly enhances the subsequent phosphorylation of p53 at Ser 18 by casein kinase I, at least under test-tube assay conditions with purified proteins.”
§ Cell cycle checkpoint signaling through the ATM and ATR kinases > References
“38. Dumaz, N., Milne D.M., and Meek D.W. 1999. Protein kinase CK1 is a p53-threonine 18 kinase which requires prior phos- phorylation of serine 15.”
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Metadata
- Authors
- Abraham, R. T.
- Affiliations
- Duke University (US)
- Corresponding author
- Abraham, Robert T.
- ORCID
- Abraham, Robert T.
- Venue
- Genes & Development
- Publisher
- Cold Spring Harbor Laboratory
- Published
- 2001-09-01
- Volume
- 15
- Issue
- 17
- Pages
- 2177-2196
- ISSN
- 0890-9369 (ISSN-L)
- 1549-5477
- OpenAlex
- W2128252882
- Semantic Scholar
- 4d2e287782bf5eb59858e4df82b3dea9790fc922
- Cited by
- 1,966
- References
- 151
- Citations by year
- 2026: 13 · 2025: 20 · 2024: 23 · 2023: 42 · 2022: 39 · 2021: 53 · 2020: 45 · 2019: 59 · 2018: 50 · 2017: 66 · 2016: 57 · 2015: 65 · 2014: 65 · 2013: 93 · 2012: 91
- Type
- posted content
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Genes & Development (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA76193, R01CA076193)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- cell cycle checkpoints, ATM kinase, ATR kinase, DNA damage response, DNA replication errors, reactive oxygen species, UV-induced DNA damage, genome stability, cancer
- MeSH terms
- Animals, DNA, Fungal Proteins, Humans, Mitosis, Models, Biological, Signal Transduction, G1 Phase, G2 Phase, S Phase, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, ATP-Binding Cassette Transporters, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, Ataxia Telangiectasia Mutated Proteins
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