Xeroderma Pigmentosa Group A (XPA), Nucleotide Excision Repair and Regulation by ATR in Response to Ultraviolet Irradiation

May combine two claims.

With either fixative, anti-XPA antibodies revealed XPA in the nucleus, but cytosolic XPA was detected only in cells fixed with cold methanol.

“We have observed that with either fixative the anti-XPA antibodies revealed XPA in the nucleus, but antibody detection of the cytosolic XPA occurred only in cells fixed with cold methanol.”

May combine two claims.

Phosphorylation of downstream proteins by ATR leads to cell cycle arrest, DNA repair activation, and apoptotic death after severe damage.

“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.”

• cites [22] Abraham RT (2001) Cell cycle checkpoint signaling through the ATM and ATR kinases, Genes Dev 15, 2177– 2196. 11544175 sourceNot checked yet

  Not checked in the free run.

• cites [34] Dart DA, Adams KE, Akerman I, and Lakin ND (2004) Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase, J Biol Chem 279, 16433– 16440. 14871897 sourceNot checked yet

  Not checked in the free run.

• cites [35] Roos WP, and Kaina B (2013) DNA damage-induced apoptosis: From specific DNA lesions to the DNA damage response and apoptosis, Cancer Lett 332, 237– 248. 22261329 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A small fraction of cellular ATR normally exists in the cytoplasm, and DNA-damaging agents increase this cytoplasmic ATR and change it to a slower-migrating ATR-H form.

“It was demonstrated that in mammals a small fraction of cellular ATR normally exists in the cytoplasm (cytoATR) and that, in response to DNA damaging agents, the amount of this cytoATR increases and changes conformation, resulting in a slower-migrating, higher electrophoretic band (ATR-H) as compared with the faster-migrating, lower electrophoretic band (ATR-L).”

• cites [40] Hilton BA, Li Z, Musich PR, Wang H, Cartwright B, Serrano MA, Zhou XZ, Lu KP, and Zou Y (2015) ATR plays a direct antiapoptotic role at mitochondria which is regulated by prolyl isomerase Pin1, Mol Cell 60, 35– 46. 26387736 PMC4592481 sourceNot checked yet

  Not checked in the free run.

• cites [41] Li Z (2013) New insights into the roles of human DNA damage checkpoint protein ATR in the regulation of nucleotide excision repair and DNA damage-induced cell death, In Biomedical Sciences, East Tennessee State University, Johnson City.Not checked yet

  Not checked in the free run.

May combine two claims.

XPA mutations cause the most severe XP deficiency because XPA is required in both global genomic and transcription-coupled nucleotide excision repair.

“XPA mutation is the most severe XP deficiency is since this protein is required in both the global genomic NER (GG-NER) and the transcription- coupled NER (TC-NER) sub-pathways of nucleotide excision repair 10–1415.”

• cites 10–1415Not checked yet

  Not checked in the free run.

May combine two claims.

UV-induced CPDs and 6-4 PPs block replication and transcription, producing single-stranded DNA stretches that become coated with RPA.

“The resulting replicative and transcriptional stresses stall DNA polymerization during replication and pol II progression in RNA synthesis11, 12, respectively, leading to an accumulation of stretches of single-strand DNA (ssDNA), which become coated with the ssDNA-binding replication protein A (RPA) 26.”

• cites [26] Zeman MK, and Cimprich KA (2014) Causes and consequences of replication stress, Nat Cell Biol 16, 2– 9. 24366029 PMC4354890 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

UV irradiation is the most efficient inducer of ATR-H formation, although camptothecin and hydroxyurea also induce it.

“The most efficient induction of ATR-H formation was by UV irradiation, though it also was induced by camptothecin and hydroxyurea, agents which cause DNA double-strand breaks (DSBs).”

• cites [40] Hilton BA, Li Z, Musich PR, Wang H, Cartwright B, Serrano MA, Zhou XZ, Lu KP, and Zou Y (2015) ATR plays a direct antiapoptotic role at mitochondria which is regulated by prolyl isomerase Pin1, Mol Cell 60, 35– 46. 26387736 PMC4592481 sourceNot checked yet

  Not checked in the free run.

• cites [41] Li Z (2013) New insights into the roles of human DNA damage checkpoint protein ATR in the regulation of nucleotide excision repair and DNA damage-induced cell death, In Biomedical Sciences, East Tennessee State University, Johnson City.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

ATR phosphorylates Chk1, which then phosphorylates other proteins to arrest cell cycle progression.

“A classic feature of ATR in response to UV damage is its phosphorylation of Chk1 kinase, which then phosphorylates other proteins to arrest cell cycle progression 51.”

• cites [51] Enders GH (2008) Expanded roles for Chk1 in genome maintenance, J Biol Chem 283, 17749– 17752. 18424430 PMC2440615 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

In the cytosolic cis isoform, the N-terminus is unfolded, exposing the BH3 domain so ATR-H can bind and sequester tBid and delay intrinsic apoptosis.

“however, the N-terminus is unfolded in the cytosolic cis-isoform which exposes this BH3 domain, allowing ATR-H to bind to and sequester tBid protein, thus delaying initiation of the intrinsic cell death pathway 40.”

• cites [40] Hilton BA, Li Z, Musich PR, Wang H, Cartwright B, Serrano MA, Zhou XZ, Lu KP, and Zou Y (2015) ATR plays a direct antiapoptotic role at mitochondria which is regulated by prolyl isomerase Pin1, Mol Cell 60, 35– 46. 26387736 PMC4592481Not checked yet

  Not checked in the free run.

May combine two claims.

Cytoplasmic ATR is free of ATRIP, which remains sequestered in the nucleus after UV irradiation.

“In contrast, Hilton et al. found that cytoATR is free of ATRIP, which remains sequestered in the nucleus after UV irradiation.”

• cites [40] Hilton BA, Li Z, Musich PR, Wang H, Cartwright B, Serrano MA, Zhou XZ, Lu KP, and Zou Y (2015) ATR plays a direct antiapoptotic role at mitochondria which is regulated by prolyl isomerase Pin1, Mol Cell 60, 35– 46. 26387736 PMC4592481Not checked yet

  Not checked in the free run.

May combine two claims.

ATR is an essential gene for nucleotide excision repair initiation and regulation and for genome maintenance.

“ATR is an essential gene for the initiation and regulation of NER and for genome maintenance 17, 36, 37.”

• cites [17] Cimprich KA, and Cortez D (2008) ATR: an essential regulator of genome integrity, Nat Rev Mol Cell Biol 9, 616– 627. 18594563 PMC2663384 sourceNot checked yet

  Not checked in the free run.

• cites [36] Brown EJ, and Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality, Genes Dev 14, 397– 402. 10691732 PMC316378 sourceNot checked yet

  Not checked in the free run.

• cites [37] Brown EJ, and Baltimore D (2003) Essential and dispensable roles of ATR in cell cycle arrest and genome maintenance, Genes Dev 17, 615– 628. 12629044 PMC196009 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ATR in complex with ATRIP binds RPA-coated single-stranded DNA through an ATRIP-RPA interaction, and ATRIP activates ATR checkpoint kinase activity.

“ATR in complex with its nuclear binding partner ATR-interacting protein (ATRIP) binds to this RPA-coated ssDNA via an ATRIP-RPA interaction. ATRIP also serves to activate the checkpoint kinase activity of ATR 4, 27–30.”

• cites [4] Sancar A, Lindsey-Boltz LA, Unsal-Kacmaz K, and Linn S (2004) Molecular mechanisms of mammalian DNA repair and the DNA damage checkpoints, Annu Rev Biochem 73, 39– 85. 15189136 sourceNot checked yet

  Not checked in the free run.

• cites [27] Cortez D, Guntuku S, Qin J, and Elledge SJ (2001) ATR and ATRIP: partners in checkpoint signaling, Science 294, 1713– 1716. 11721054 sourceNot checked yet

  Not checked in the free run.

• cites [28] Choi JH, Sancar A, and Lindsey-Boltz LA (2009) The human ATR-mediated DNA damage checkpoint in a reconstituted system, Methods 48, 3– 7. 19245835 sourceNot checked yet

  Not checked in the free run.

• cites [29] Zou L, and Elledge SJ (2003) Sensing DNA damage through ATRIP recognition of RPA- ssDNA complexes, Science 300, 1542– 1548. 12791985 sourceNot checked yet

  Not checked in the free run.

• cites [30] Zou L, Liu D, and Elledge SJ (2003) Replication protein A-mediated recruitment and activation of Rad17 complexes, Proc Natl Acad Sci USA 100, 13827– 13832. 14605214 PMC283506 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ATR-L is the prolyl trans-isomer of cytoplasmic ATR, while ATR-H is the cis-isomer.

“It was found that the ATR-L is a prolyl trans-isomer of cytoplasmic ATR while ATR-H is the cis-isomer 40.”

• cites [40] Hilton BA, Li Z, Musich PR, Wang H, Cartwright B, Serrano MA, Zhou XZ, Lu KP, and Zou Y (2015) ATR plays a direct antiapoptotic role at mitochondria which is regulated by prolyl isomerase Pin1, Mol Cell 60, 35– 46. 26387736 PMC4592481Not checked yet

  Not checked in the free run.

May combine two claims.

Nuclear ATR remains ATR-L regardless of UV, and its BH3 domain appears masked in the folded N-terminal region of the trans isoform.

“In the nucleus, ATR remains in the form of ATR-L, regardless of UV, whose BH3 domain appears to be masked in a folded N-terminal region of the trans- isoform protein;”

• cites [40] Hilton BA, Li Z, Musich PR, Wang H, Cartwright B, Serrano MA, Zhou XZ, Lu KP, and Zou Y (2015) ATR plays a direct antiapoptotic role at mitochondria which is regulated by prolyl isomerase Pin1, Mol Cell 60, 35– 46. 26387736 PMC4592481Not checked yet

  Not checked in the free run.

May combine two claims.

XPC mutations are less severe than XPA mutations because XPC acts mainly in global genomic nucleotide excision repair.

“XPC mutations, though relatively frequent, are less severe since this protein is primarily involved in GG-NER 10,16.”

• cites [10] Gillet LC, and Scharer OD (2006) Molecular mechanisms of mammalian global genome nucleotide excision repair, Chem Rev 106, 253– 276. 16464005 sourceNot checked yet

  Not checked in the free run.

• cites [16] Sugasawa K (2008) XPC: its product and biological roles, Adv Exp Med Biol 637, 47– 56. 19181110 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Importin-α7 functions independently of DNA damage and ATR kinase activation, perhaps reflecting G2-phase XPA import.

“In contrast, importin-α7 functioned independent of DNA damage and ATR kinase activation, perhaps reflecting the observed nuclear import of XPA in the G2 phase irrespective of UV exposure 69.”

• cites [68] Li Z, Musich PR, Cartwright BM, Wang H, and Zou Y (2013) UV-induced nuclear import of XPA is mediated by importin-alpha4 in an ATR-dependent manner, PloS One 8, e68297. 23861882 PMC3704644 sourceNot checked yet

  Not checked in the free run.

• cites [69] Li Z, Musich PR, Serrano MA, Dong Z, and Zou Y (2011) XPA-mediated regulation of global nucleotide excision repair by ATR Is p53-dependent and occurs primarily in S- phase, PloS One 6, e28326. 22174788 PMC3236200 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

ATR binds XPA via the Lys188 and Ser196 residues in its helix-turn-helix motif, and these residues are important for efficient CPD repair.

“Recall that ATR binds to XPA via the Lys188 and Ser196 residues in its HTH motif containing 53 and that these residues are important for the efficient repair of CPD adducts.”

• cites [53] Shell SM, and Zou Y (2009) Protein-protein interactions in Ataxia telangiectesia, In Molecular Mechanisms of Ataxia Telangiectasia (Ahmad S, and Hanaoka F, Eds.), pp 42– 51, Landes Bioscience.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Maximum UV-induced phosphorylation of p53 Ser15 and the most efficient NER removal of CPD adducts both occur in S phase.

“Li et al. observed that the maximum UV-induced phosphorylation of Ser15 of p53 occurred in S phase and that the NER removal of CPD adducts also was most efficient in S phase 69.”

• cites [69] Li Z, Musich PR, Serrano MA, Dong Z, and Zou Y (2011) XPA-mediated regulation of global nucleotide excision repair by ATR Is p53-dependent and occurs primarily in S- phase, PloS One 6, e28326. 22174788 PMC3236200Not checked yet

  Not checked in the free run.

May combine two claims.

Nuclear import of XPA after UV irradiation or cisplatin treatment is ATR-dependent in normal fibroblasts and p53-proficient cancer cells, and also depends on p53 transcriptional activity.

“Li et al. demonstrated that the nuclear import of XPA in response to UV irradiation or cisplatin treatment is ATR-dependent in normal fibroblasts and in cancer cells that are p53 proficient; XPA import also is dependent on the transcriptional activity of p53 in these cells 69, 70.”

• cites [69] Li Z, Musich PR, Serrano MA, Dong Z, and Zou Y (2011) XPA-mediated regulation of global nucleotide excision repair by ATR Is p53-dependent and occurs primarily in S- phase, PloS One 6, e28326. 22174788 PMC3236200 sourceNot checked yet

  Not checked in the free run.

• cites [70] Li Z, Musich PR, and Zou Y (2011) Differential DNA damage responses in p53 proficient and deficient cells: cisplatin-induced nuclear import of XPA is independent on ATR checkpoint in p53-deficient lung cancer cells, Int J Biochem Mol Biol 2, 138– 145. 21643554 PMC3107498Not checked yet

  Not checked in the free run.

May combine two claims.

XPA occurs predominantly in the cytoplasm of normal mammalian cells and is translocated to the nucleus after DNA damage, especially UV irradiation.

“However, biochemical fractionation of millions of cells into nuclear vs. cytoplasmic fractions revealed that XPA occurs predominantly in the cytoplasm of normal mammalian cells and that it is translocated to the nucleus in response to DNA damage, especially from UV irradiation 67–70.”

• cites [67] Wu X, Shell SM, Liu Y, and Zou Y (2007) ATR-dependent checkpoint modulates XPA nuclear import in response to UV irradiation, Oncogene 26, 757– 764. 16862173 PMC3106104 sourceNot checked yet

  Not checked in the free run.

• cites [68] Li Z, Musich PR, Cartwright BM, Wang H, and Zou Y (2013) UV-induced nuclear import of XPA is mediated by importin-alpha4 in an ATR-dependent manner, PloS One 8, e68297. 23861882 PMC3704644 sourceNot checked yet

  Not checked in the free run.

• cites [69] Li Z, Musich PR, Serrano MA, Dong Z, and Zou Y (2011) XPA-mediated regulation of global nucleotide excision repair by ATR Is p53-dependent and occurs primarily in S- phase, PloS One 6, e28326. 22174788 PMC3236200 sourceNot checked yet

  Not checked in the free run.

• cites [70] Li Z, Musich PR, and Zou Y (2011) Differential DNA damage responses in p53 proficient and deficient cells: cisplatin-induced nuclear import of XPA is independent on ATR checkpoint in p53-deficient lung cancer cells, Int J Biochem Mol Biol 2, 138– 145. 21643554 PMC3107498Not checked yet

  Not checked in the free run.

May combine two claims.

ATR-H reaches a maximum within 2 hours but persists in the cytoplasm for over 8 hours.

“Note that, once formed, ATR-H reaches a maximum within 2 hours but persists in the cytoplasm for over 8 hours, sufficient time for most NER-competent cells to repair all the (6–4) PP adducts and most, if not all, of the CPD adducts 40, 53,41.”

• cites [40] Hilton BA, Li Z, Musich PR, Wang H, Cartwright B, Serrano MA, Zhou XZ, Lu KP, and Zou Y (2015) ATR plays a direct antiapoptotic role at mitochondria which is regulated by prolyl isomerase Pin1, Mol Cell 60, 35– 46. 26387736 PMC4592481 sourceNot checked yet

  Not checked in the free run.

• cites [53] Shell SM, and Zou Y (2009) Protein-protein interactions in Ataxia telangiectesia, In Molecular Mechanisms of Ataxia Telangiectasia (Ahmad S, and Hanaoka F, Eds.), pp 42– 51, Landes Bioscience.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

• cites [41] Li Z (2013) New insights into the roles of human DNA damage checkpoint protein ATR in the regulation of nucleotide excision repair and DNA damage-induced cell death, In Biomedical Sciences, East Tennessee State University, Johnson City.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Methanol fixation extracts lipids, dehydrates and permeabilizes cells, causing proteins to denature and precipitate, whereas paraformaldehyde fixation cross-links proteins and macromolecules in place.

“Methanol fixation extracts lipids, dehydrates and permeablizes cells causing proteins to denature and precipitate onto the cellular architecture. In contrast, para-formaldehyde fixation cross-links proteins and other macromolecules in place 71.”

• cites [71] Schnell U, Dijk F, Sjollema KA, and Giepmans BNG (2012) Immunolabeling artifacts and the need for live-cell imaging, Nat Meth 9, 152– 158. 22290187 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Nuclear import of cytosolic XPA depends on p53 transcriptional activity in p53+/+ cells and occurs much more slowly in p53−/− cells, but still occurs.

“Consistently, nuclear import of cytosolic XPA is dependent on p53 transcriptional activity in p53+/+ cells and occurs much slower in p53−/− cells, but the import stills occurs 70.”

• cites [70] Li Z, Musich PR, and Zou Y (2011) Differential DNA damage responses in p53 proficient and deficient cells: cisplatin-induced nuclear import of XPA is independent on ATR checkpoint in p53-deficient lung cancer cells, Int J Biochem Mol Biol 2, 138– 145. 21643554 PMC3107498Not checked yet

  Not checked in the free run.

May combine two claims.

A Lys188Ala mutation disrupts the ATR-XPA interaction and significantly reduces DNA repair efficiency.

“Shell’s structure-function studies also found that the Lys188 residue, which is nearby in the same helical DBD of XPA, was critical since a Lys188Ala mutation disrupted the ATR-XPA interaction, thus significantly reducing DNA repair efficiency 81.”

• cites [81] Shell SM, Li Z, Shkriabai N, Kvaratskhelia M, Brosey C, Serrano MA, Chazin WJ, Musich PR, and Zou Y (2009) Checkpoint kinase ATR promotes nucleotide excision repair of UV-induced DNA damage via physical interaction with Xeroderma Pigmentosum Group A, J Biol Chem 284, 24213– 24222. 19586908 PMC2782015 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Most XPA remains cytosolic in G1 even after UV treatment, whereas in G2-phase cells most XPA is nuclear regardless of UV irradiation.

“Most XPA remained sequestered in the cytosol in the G1 phase even after UV treatment; in contrast, in G2-phase cells the nucleus contained the majority of the XPA molecules irrespective of UV irradiation.”

• cites [69] Li Z, Musich PR, Serrano MA, Dong Z, and Zou Y (2011) XPA-mediated regulation of global nucleotide excision repair by ATR Is p53-dependent and occurs primarily in S- phase, PloS One 6, e28326. 22174788 PMC3236200Not checked yet

  Not checked in the free run.

May combine two claims.

Efficient NER removal of damage depends on ATR kinase activity in p53-proficient cells, but the repair process appears ATR-independent in p53-deficient cells.

“Although efficient NER removal of the damage was dependent on ATR kinase activity in p53-proficient (p53+/+) cells the repair process seemed to be ATR-independent in p53-deficient (p53−/−) cells 69, 70, 77.”

• cites [69] Li Z, Musich PR, Serrano MA, Dong Z, and Zou Y (2011) XPA-mediated regulation of global nucleotide excision repair by ATR Is p53-dependent and occurs primarily in S- phase, PloS One 6, e28326. 22174788 PMC3236200 sourceNot checked yet

  Not checked in the free run.

• cites [70] Li Z, Musich PR, and Zou Y (2011) Differential DNA damage responses in p53 proficient and deficient cells: cisplatin-induced nuclear import of XPA is independent on ATR checkpoint in p53-deficient lung cancer cells, Int J Biochem Mol Biol 2, 138– 145. 21643554 PMC3107498Not checked yet

  Not checked in the free run.

• cites [77] Auclair Y, Rouget R, Affar el B, and Drobetsky EA (2008) ATR kinase is required for global genomic nucleotide excision repair exclusively during S phase in human cells, Proc Natl Acad Sci U S A 105, 17896– 17901. 19004803 PMC2584713 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

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.”

• cites [73] Ray A, Blevins C, Wani G, and Wani AA (2016) ATR- and ATM-Mediated DNA damage response is dependent on excision repair assembly during G1 but bot in S phase of cell cycle, PLoS One 11, e0159344. 27442013 PMC4956099 sourceNot checked yet

  Not checked in the free run.

• cites [74] Ray A, Milum K, Battu A, Wani G, and Wani AA (2013) NER initiation factors, DDB2 and XPC, regulate UV radiation response by recruiting ATR and ATM kinases to DNA damage sites, DNA Repair 12, 273– 283. 23422745 PMC4174315 sourceNot checked yet

  Not checked in the free run.

• cites [75] Lindsey-Boltz LA, Kemp MG, Reardon JT, DeRocco V, Iyer RR, Modrich P, and Sancar A (2014) Coupling of human DNA excision repair and the DNA damage checkpoint in a defined in vitro system, J Biol Chem 289, 5074– 5082. 24403078 PMC3931066 sourceNot checked yet

  Not checked in the free run.

• cites [76] Kemp MG, Gaddameedhi S, Choi JH, Hu J, and Sancar A (2014) DNA repair synthesis and ligation affect the processing of excised oligonucleotides generated by human nucleotide excision repair, J Biol Chem 289, 26574– 26583. 25107903 PMC4176238 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

A Ser196Ala mutation in XPA significantly reduces repair efficiency of CPDs but not of 6-4 PPs.

“In addition, disruption of this phosphorylation site in XPA with a Ser196Ala mutation significantly reduced the repair efficiency of CPDs but not the repair of (6–4) PPs.”

• cites [53] Shell SM, and Zou Y (2009) Protein-protein interactions in Ataxia telangiectesia, In Molecular Mechanisms of Ataxia Telangiectasia (Ahmad S, and Hanaoka F, Eds.), pp 42– 51, Landes Bioscience.Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Importin-α4 transport of XPA is activated by UV radiation and requires functional ATR kinase activity, consistent with S-phase nuclear import.

“Importin-α4 transport of XPA was activated by UV radiation and required functional ATR kinase activity, consistent with importin-α4 being responsible for the nuclear import of XPA during the S-phase DNA damage response.”

• cites [68] Li Z, Musich PR, Cartwright BM, Wang H, and Zou Y (2013) UV-induced nuclear import of XPA is mediated by importin-alpha4 in an ATR-dependent manner, PloS One 8, e68297. 23861882 PMC3704644 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

The peak activity of ATR occurs in S phase during normal DNA replication and in response to DNA damage.

“Regulation of S-phase cytosolic XPA translocation into the nucleus by ATR is consistent with previous findings that the peak activity of this checkpoint kinase occurs in S phase as part of normal DNA replication and also in response to DNA damage 34, 77.”

• cites [34] Dart DA, Adams KE, Akerman I, and Lakin ND (2004) Recruitment of the cell cycle checkpoint kinase ATR to chromatin during S-phase, J Biol Chem 279, 16433– 16440. 14871897 sourceNot checked yet

  Not checked in the free run.

• cites [77] Auclair Y, Rouget R, Affar el B, and Drobetsky EA (2008) ATR kinase is required for global genomic nucleotide excision repair exclusively during S phase in human cells, Proc Natl Acad Sci U S A 105, 17896– 17901. 19004803 PMC2584713 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Normal UV-induced nuclear translocation of cytosolic XPA is lost with the Lys188Ala mutation, while the Ser196Ala mutation has no effect on XPA nuclear translocation.

“Moreover, the normal UV- induced nuclear translocation of cytosolic XPA was lost with the Lys188Ala mutation. However, the Ser196Ala mutation had no effect on XPA’s nuclear translocation.”

• cites [81] Shell SM, Li Z, Shkriabai N, Kvaratskhelia M, Brosey C, Serrano MA, Chazin WJ, Musich PR, and Zou Y (2009) Checkpoint kinase ATR promotes nucleotide excision repair of UV-induced DNA damage via physical interaction with Xeroderma Pigmentosum Group A, J Biol Chem 284, 24213– 24222. 19586908 PMC2782015 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Importin-α4 and importin-α7 are required for XPA nuclear import, but other importin-α proteins are not.

“In addition, siRNA knockdown revealed that nucleo- cytoplasmic transport proteins importin-α4 and -α7 were required for XPA nuclear import, but not the other importin-α proteins.”

• cites [68] Li Z, Musich PR, Cartwright BM, Wang H, and Zou Y (2013) UV-induced nuclear import of XPA is mediated by importin-alpha4 in an ATR-dependent manner, PloS One 8, e68297. 23861882 PMC3704644 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

Depletion of XPA in aging HGPS cells significantly relieves the deficiency in DSB repair, possibly by shifting available free PCNA to XPA-free junctions.

“Depletion of XPA in these aging HGPS cells significantly relieves the deficiency in DSB repair, possibly by shifting the binding of available free PCNA to these XPA-free junctions (Hilton et al., private communication).”

• cites Hilton et al., private communicationNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

Fang et al. reported increased PARP1 activity, higher protein parsylation, NAD+ depletion, and reduced mitochondrial energy generation in XPA−/− cells.

“They also reported increased poly(ADP-ribose) polymerase 1 (PARP1) activity, resulting in higher parsylation of cellular proteins resulting in NAD+ depletion, thus reducing mitochondrial energy generation.”

• cites [90] Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, Mitchell JR, Croteau DL, and Bohr VA (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction, Cell 157, 882– 896. 24813611 PMC4625837 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

HGPS patients suffer laminopathy due to a sporadic deficiency in proteolytic processing of prelamin A into mature lamin A.

“Hutchison-Gilford progeria syndrome (HGPS) patients suffer from a variety of laminopathy ailments due to a sporadic deficiency in the proteolytic processing of the precursor form of lamin A into the mature protein.”

• cites [105] Dechat T, Adam SA, Taimen P, Shimi T, and Goldman RD (2010) Nuclear Lamins, Cold Spring Harb Perspect Biol 2, 1– 22. PMC2964183 20826548 sourceNot checked yet

  Not checked in the free run.

• cites [106] Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, and Collins FS (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome, Proc Natl Acad Sci U S A 101, 8963– 8968. 15184648 PMC428455 sourceNot checked yet

  Not checked in the free run.

• cites [107] Kudlow BA, Kennedy BK, and Monnat RJ Jr. (2007) Werner and Hutchinson- Gilford progeria syndromes: mechanistic basis of human progeroid diseases, Nat Rev Mol Cell Biol 8, 394– 404. 17450177 sourceNot checked yet

  Not checked in the free run.

• cites [108] Misteli T, and Scaffidi P (2005) Genome instability in progeria: when repair gets old, Nat Med 11, 718– 719. 16015360 sourceNot checked yet

  Not checked in the free run.

• cites [109] Musich PR, and Zou Y (2009) Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A, Impact Aging 1, 28– 37. PMC2765059 19851476 sourceNot checked yet

  Not checked in the free run.

• cites [110] Pereira S, Bourgeois P, Navarro C, Esteves-Vieira V, Cau P, De Sandre-Giovannoli A, and Lévy N (2008) HGPS and related premature aging disorders: From genomic identification to the first therapeutic approaches, Mech Ageing Dev 129, 449– 459. 18513784 sourceNot checked yet

  Not checked in the free run.

• cites [111] Smith ED, Kudlow BA, Frock RL, and Kennedy BK (2005) A-type nuclear lamins, progerias and other degenerative disorders, Mech Ageing Dev 126, 447– 460. 15722103 sourceNot checked yet

  Not checked in the free run.

• cites [112] Wiesel N, Mattout A, Melcer S, Melamed-Book N, Herrmann H, Medalia O, Aebi U, and Gruenbaum Y (2008) Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins, Proc Natl Acad Sci U S A 105, 180– 185. 18162544 PMC2224182 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

XPA binding may limit access to DSB repair proteins but could stabilize forks and prevent progerin-induced apoptosis in HGPS cells.

“Although this XPA binding may limit access to DNA DSBs repair proteins, it appears that the binding could stabilize the forks and prevent the HGPS cells from progerin-induced apoptosis (Hilton et al., private communication).”

• cites Hilton et al., private communicationNot checked yet

  Not checked in the free run.

May combine two claims.

XPA misaccumulates at DSB sites consisting of ds-ssDNA junctions even though XPA has no documented role in DSB repair, causing these breaks to become progressively devoid of DSB repair proteins.

“Interestingly, cellular nucleotide excision repair protein XPA misaccumulates at the DSB sites consisting of ds-ssDNA junctions even though XPA never has had a documented role in DSB repair, causing these breaks to become progressively devoid of DSB repair proteins 114.”

• cites [114] Liu Y, Wang Y, Rusinol AE, Sinensky MS, Liu J, Shell SM, and Zou Y (2008) Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J 22, 603– 611. 17848622 PMC3116236 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

HGPS cells with progerin accumulation have a reduced replicative lifespan and a deficiency in repairing endogenous laminopathy-induced DNA double-strand breaks, which increase with age.

“HGPS cells with progerin accumulation exhibit a reduced replicative lifespan plus a deficiency in the repair of endogenous, laminopathy-induced DNA DSBs, which increase with age 113, 114.”

• cites [113] Liu Y, Rusinol A, Sinensky M, Wang Y, and Zou Y (2006) DNA damage responses in progeroid syndromes arise from defective maturation of prelamin A, J Cell Sci 119, 4644– 4649. 17062639 PMC3105909 sourceNot checked yet

  Not checked in the free run.

• cites [114] Liu Y, Wang Y, Rusinol AE, Sinensky MS, Liu J, Shell SM, and Zou Y (2008) Involvement of Xeroderma pigmentosum group A (XPA) in progeria arising from defective maturation of prelamin A, FASEB J 22, 603– 611. 17848622 PMC3116236 sourceNot checked yet

  Not checked in the free run.

Probably not a substantial claim: may not pass S3 (load-bearing).

Progerin is a truncated lamin A with a hydrophobic farnesylated C-terminal.

“The aberrantly processed protein produced is called progerin, a truncated form of lamin A with a hydrophobic farnesylated C-terminal 105–112.”

• cites [105] Dechat T, Adam SA, Taimen P, Shimi T, and Goldman RD (2010) Nuclear Lamins, Cold Spring Harb Perspect Biol 2, 1– 22. PMC2964183 20826548 sourceNot checked yet

  Not checked in the free run.

• cites [106] Goldman RD, Shumaker DK, Erdos MR, Eriksson M, Goldman AE, Gordon LB, Gruenbaum Y, Khuon S, Mendez M, Varga R, and Collins FS (2004) Accumulation of mutant lamin A causes progressive changes in nuclear architecture in Hutchinson-Gilford progeria syndrome, Proc Natl Acad Sci U S A 101, 8963– 8968. 15184648 PMC428455 sourceNot checked yet

  Not checked in the free run.

• cites [107] Kudlow BA, Kennedy BK, and Monnat RJ Jr. (2007) Werner and Hutchinson- Gilford progeria syndromes: mechanistic basis of human progeroid diseases, Nat Rev Mol Cell Biol 8, 394– 404. 17450177 sourceNot checked yet

  Not checked in the free run.

• cites [108] Misteli T, and Scaffidi P (2005) Genome instability in progeria: when repair gets old, Nat Med 11, 718– 719. 16015360 sourceNot checked yet

  Not checked in the free run.

• cites [109] Musich PR, and Zou Y (2009) Genomic instability and DNA damage responses in progeria arising from defective maturation of prelamin A, Impact Aging 1, 28– 37. PMC2765059 19851476 sourceNot checked yet

  Not checked in the free run.

• cites [110] Pereira S, Bourgeois P, Navarro C, Esteves-Vieira V, Cau P, De Sandre-Giovannoli A, and Lévy N (2008) HGPS and related premature aging disorders: From genomic identification to the first therapeutic approaches, Mech Ageing Dev 129, 449– 459. 18513784 sourceNot checked yet

  Not checked in the free run.

• cites [111] Smith ED, Kudlow BA, Frock RL, and Kennedy BK (2005) A-type nuclear lamins, progerias and other degenerative disorders, Mech Ageing Dev 126, 447– 460. 15722103 sourceNot checked yet

  Not checked in the free run.

• cites [112] Wiesel N, Mattout A, Melcer S, Melamed-Book N, Herrmann H, Medalia O, Aebi U, and Gruenbaum Y (2008) Laminopathic mutations interfere with the assembly, localization, and dynamics of nuclear lamins, Proc Natl Acad Sci U S A 105, 180– 185. 18162544 PMC2224182 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

These DNA metabolism deficiencies correlate with proteolytic truncation of RFC1 and sequestration of PCNA in a complex with progerin.

“These DNA metabolism deficiencies also correlate with a proteolytic truncation of replication factor C1 (RFC1) 115 and a sequestration of proliferating cell nuclear antigen (PCNA) in a complex with progerin (Hilton et al., private communication).”

• cites [115] Tang H, Hilton B, Musich PR, Fang DZ, and Zou Y (2011) Replication factor C1, the large subunit of replication factor C, is proteolytically truncated in Hutchinson-Gilford Progeria Syndrome, Aging Cell 11, 363– 365. PMC3306506 22168243 sourceNot checked yet

  Not checked in the free run.

• cites Hilton et al., private communicationNot matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

May combine two claims.

Fang et al. observed that the XPA−/− phenotype includes neurological features similar to mitochondrial diseases and abnormal mitochondrial energy metabolism, even though cytoplasmic XPA in XPA-proficient cells was absent from the mitochondrial matrix.

“Using a bioinformatics analysis Fang et al. observed that the XPA−/− phenotype includes neurological features similar to mitochondrial diseases, and results in abnormal mitochondrial energy metabolism, even though cytoplasmic XPA in XPA-proficient cells was absent from the mitochondrial matrix 90.”

• cites [90] Fang EF, Scheibye-Knudsen M, Brace LE, Kassahun H, SenGupta T, Nilsen H, Mitchell JR, Croteau DL, and Bohr VA (2014) Defective mitophagy in XPA via PARP-1 hyperactivation and NAD(+)/SIRT1 reduction, Cell 157, 882– 896. 24813611 PMC4625837 sourceNot checked yet

  Not checked in the free run.

May combine two claims.

As HGPS cells age, progerin accumulates and sequesters PCNA, producing collapsed replication forks with DSBs and ds-ssDNA junctions to which XPA binds.

“These observations suggest that as HGPS cells age progerin accumulates and sequesters PCNA, resulting in collapsed replication forks with DSBs and ds-ssDNA junctions to which XPA binds.”

May combine two claims.

The subcellular distribution of XPA is detectable by immunofluorescence microscopy after cold methanol fixation, but not after p-formaldehyde fixation.

“This subcellular distribution can be easily detected by immunofluorescence microscopy if the cells are fixed in cold methanol but not in cells fixed with p-formaldehyde.”

Probably not a substantial claim: may not pass S3 (load-bearing).

PARP1 activation can be induced by stress responses other than DNA damage, including ERK-1, Notch/HES-1, and intracellular calcium overload.

“In addition, as reviewed by Weaver and Yang 94, PARP1 activation can be induced by stress responses other than DNA damage, including the ERK-1 95, 96 and Notch/HES-1 97 signaling pathways and intracellular calcium overload 98.”

• cites [94] Weaver AN, and Yang ES (2013) Beyond DNA repair: Additional functions of PARP-1 in cancer, Front Oncol 3, 290. 24350055 PMC3841914 sourceNot checked yet

  Not checked in the free run.

• cites [95] Cohen-Armon M (2007) PARP-1 activation in the ERK signaling pathway, Trends Pharmacol Sci 28, 556– 560. 17950909 sourceNot checked yet

  Not checked in the free run.

• cites [96] Cohen-Armon M, Visochek L, Rozensal D, Kalal A, Geistrikh I, Klein R, Bendetz- Nezer S, Yao Z, and Seger R (2007) DNA-independent PARP-1 activation by phosphorylated ERK2 increases Elk1 activity: A link to histone acetylation, Mol Cell 25, 297– 308. 17244536 sourceNot checked yet

  Not checked in the free run.

• cites [97] Kannan S, Fang W, Song G, Mullighan CG, Hammitt R, McMurray J, and Zweidler- McKay PA (2016) Notch/HES1-mediated PARP1 activation: a cell type–specific mechanism for tumor suppression, Blood 117, 2891– 2900. PMC3062299 21224467 sourceNot checked yet

  Not checked in the free run.

Classified as probably not a substantial claim.

Progerin is an abnormal form of lamin A.

“an abnormal form of lamin A”

The quote only partly states this claim.

Sequestration of tBid by unfolded ATR prevents the initiation of intrinsic apoptosis, thereby allowing time for DNA repair.

“to prevent initiation of the intrinsic apoptosis, thus allowing time for DNA repair”

Probably not a substantial claim: may not pass S3 (load-bearing).

ATR kinase activates p53.

“which also is activated by the ATR kinase”