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Cited by 43DNA Repair MechanismsDNA and Nucleic Acid ChemistryNuclear Structure and Function

Mind the gap: keeping UV lesions in check

Open access
Novarina, Daniele, Amara, Flavio, Lazzaro, Federico, Plevani, Paolo, Muzi-Falconi, Marco·2011·DNA Repair
DOI 10.1016/j.dnarep.2011.04.030PMC PMC3171152
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Abstract

Cells respond to genotoxic insults by triggering a DNA damage checkpoint surveillance mechanism and by activating repair pathways. Recent findings indicate that the two processes are more related than originally thought. Here we discuss the mechanisms involved in responding to UV-induced lesions in different phases of the cell cycle and summarize the most recent data in a model where Nucleotide Excision Repair (NER) and exonucleolytic activities act in sequence leading to checkpoint activation in non replicating cells. The critical trigger is likely represented by problematic intermediates that cannot be completely or efficiently repaired by NER. In S phase cells, on the other hand, the replicative polymerases, blocked by bulky UV lesions, re-initiate DNA synthesis downstream of the lesions, leaving behind a ssDNA tract. If these gaps are not rapidly refilled, checkpoint kinases will be activated.

AI snapshot

Written from the paper’s full text.

TL;DR

This review argues that UV lesions activate DNA damage checkpoints mainly after repair or replication converts them into RPA-coated single-stranded DNA, not because the lesions themselves are directly sensed. It integrates yeast and human data to describe a two-way relationship in which NER, Exo1, translesion synthesis, and checkpoint kinases influence each other across G1, S, and G2/M.

Key findings

  • In non-replicating cells, UV photoproducts alone are insufficient for checkpoint activation; NER incision plus Exo1 nuclease activity generates long ssDNA that recruits Mec1/ATR and the 9-1-1 clamp. Normal NER gaps are about 30 nt and are rapidly filled, with repair synthesis estimated at roughly 3700 nt/min versus Exo1 at about 160 nt/min, so checkpoint activation occurs when gap filling is impaired or at higher doses such as >20 J/m2.
  • In S phase, blocked replicative polymerases re-initiate downstream of lesions, leaving ssDNA gaps; low UV (5 J/m2) produces a post-replication checkpoint in yeast, and NER-deficient yeast arrest at S phase even at 5 J/m2. Under chronic low UV (0.18 J m−2 min−1), survival depends on the RAD5-dependent branch of post-replication repair rather than NER or checkpoint function.
  • NER proteins help recruit checkpoint factors: yeast Rad14 interacts with 9-1-1 subunits, human XPA and XPC are needed for 9-1-1 recruitment, Cep164 is recruited via XPA, and ATM associates with NER factors after cisplatin. Conversely, checkpoint kinases modulate NER through Rad9, Rad26/CSB, XPA, DDB2/Claspin, and ATR-dependent S-phase GG-NER.
  • Closely opposing UV lesions, measured at about 1% of UV-induced lesions, may stall repair synthesis and promote Exo1 processing and checkpoint signaling; translesion polymerases counteract the checkpoint signal, and DNA polymerase κ contributes approximately 30% of unscheduled DNA synthesis in UV-irradiated human cells.

Methods

  • Narrative review with no primary experimental data; it synthesizes published studies on UV damage, nucleotide excision repair, post-replication repair/translesion synthesis, and DNA damage checkpoint signaling.
  • Draws on yeast and mammalian cell systems, including non-cycling and cycling cells, mutant strains such as rad14, mec1, rad18, rad5, and XP/CS patient cells, and cited measurements of UV doses, repair rates, and protein interactions.
  • Main analysis is conceptual model building, using cited literature to propose sequential and reciprocal mechanisms rather than reporting new experiments.

Limitations

  • Stated in the paper: the physiological significance of the Rad14–9-1-1 interaction has not been fully addressed; the human Rad9 orthologue remains debated; the role of translesion polymerases in NER is not completely understood; chronic low UV findings in yeast contrast with NER-deficient XP photosensitivity and need extension beyond yeast; and some ATR/XPA roles require further study.
  • Evident from the text: as a review, its conclusions depend on cited studies and a proposed model, with no new experimental validation; several mechanisms are inferred largely from yeast and may not fully translate to mammalian cells.

Model-written summary. Check it against the paper before relying on it.

Integrity signals

Registry

Crossref · 10.1016/j.dnarep.2011.04.030

Cites

108 of 108 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 153 cited sources checked · 0 supported · 0 flagged

  • Interpretationreasoning

    The checkpoint trigger in non-replicating cells is likely problematic repair intermediates that NER cannot fully or efficiently repair.

    “The critical trigger is likely represented by problematic intermediates that cannot be completely or efficiently repaired by NER.”
    Quote in the paperNot a substantial claim
  • Premisecitation

    Mutations in checkpoint genes cause syndromes with increased cancer proneness or other clinical symptoms, especially neurological defects.

    “The importance of the DNA damage checkpoint in the maintenance of genomic stability is underlined by the existence of many syndromes linked to mutations in checkpoint genes, causing increased cancer proneness or other clinical symptoms, especially neurological defects [13,14]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [13] Kastan M.B. Bartek J. Cell-cycle checkpoints and cancer Nature 432 2004 316 323 15549093 source

      Not checked in the free run.

    • cites [14] Kerzendorfer C. O’Driscoll M. Human DNA damage response and repair deficiency syndromes: linking genomic instability and cell cycle checkpoint proficiency DNA Repair (Amst) 8 2009 1139 1152 19473885 source

      Not checked in the free run.

  • Premisereasoning

    Checkpoint activation temporarily delays or halts cell cycle progression, potentially allowing removal of DNA lesions before they become more dangerous secondary lesions.

    “Checkpoint activation temporarily halts or delays cell cycle progression, possibly providing the cell with enough time to remove DNA lesions before these are converted in secondary and more dangerous lesions (e.g., replication through a single strand gap would generate a double strand break).”
    Quote in the paperSubstantial claim
  • Premisecitation

    Checkpoint factors are recruited to a common DNA intermediate identified as long RPA-covered ssDNA.

    “Given the variety of DNA lesions the cell has to deal with, it was hypothesized that the first responders, among checkpoint factors, had to be recruited to a common DNA intermediate, which was later identified as long regions of ssDNA covered by RPA [44].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [44] Zou L. Elledge S.J. Sensing DNA damage through ATRIP recognition of RPA–ssDNA complexes Science 300 2003 1542 1548 12791985 source

      Not checked in the free run.

  • Interpretationreasoning

    If the ssDNA gaps left after re-priming are not rapidly refilled, checkpoint kinases become activated.

    “If these gaps are not rapidly refilled, checkpoint kinases will be activated.”
    Quote in the paperNot a substantial claim
  • May combine two claims. 58
  • Classified as probably not a substantial claim. 6

  • May combine two claims.

    Premisecitation

    In human cells, ATM is activated by double-strand breaks such as those caused by ionizing radiation, while ATR is activated by RPA-coated ssDNA and mainly triggers checkpoint activation after UV irradiation or replication stress.

    “In fact, ATM (Ataxia Telangiectasia Mutated) is activated by double-strand breaks (DSBs) caused, for example, by ionizing radiation (IR), while ATR (ATM and Rad3-Related) is activated by ssDNA coated with the RPA heterotrimeric complex and mainly triggers checkpoint activation after UV irradiation or replication-stress.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [37] Khanna K.K. Lavin M.F. Ionizing-radiation and UV induction of p53 protein by different pathways in ataxia–telangiectasia cells Oncogene 8 1993 3307 3312 8247533

      Not checked in the free run.

    • cites [38] Tibbetts R.S. Brumbaugh K.M. A role for ATR in the DNA damage-induced phosphorylation of p53 Genes Dev. 13 1999 152 157 9925639 PMC316393 source

      Not checked in the free run.

    • cites [39] Canman C.E. Lim D.S. Activation of the ATM kinase by ionizing radiation and phosphorylation of p53 Science 281 1998 1677 1679 9733515 source

      Not checked in the free run.

    • cites [40] Lovejoy C.A. Cortez D. Common mechanisms of PIKK regulation DNA Repair (Amst) 8 2009 1004 1008 19464237 PMC2725225 source

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  • May combine two claims.

    Premisecitation

    Such ssDNA gaps have been detected by electron microscopy on replicating UV-damaged DNA and are likely responsible for the rapid and sensitive response in UV-irradiated S phase cells.

    “Such structures have been detected by electron microscopy on replicating UV-damaged DNA and are likely responsible for the rapid and sensitive response observed in UV-irradiated S phase cells [51].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [51] Lopes M. Foiani M. Sogo J.M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions Mol. Cell 21 2006 15 27 16387650 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UV-induced lesions are mainly removed by NER, which recognizes 6-4PPs efficiently and CPDs more slowly.

    “UV-induced DNA lesions are mainly removed through NER that efficiently identifies 6-4PPs and more slowly takes care of CPDs.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Friedberg E.C. Walker G.C. Siede W. DNA repair and mutagenesis 2006 ASM Press Washington, D.C.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chk1 activation also requires Rad9, but the mechanism by which Rad9 facilitates Chk1 phosphorylation by Mec1 is poorly understood.

    “Chk1 activation also requires Rad9, but the mechanism through which this mediator facilitates Chk1 phosphorylation by Mec1 is still poorly understood [30].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [30] Blankley R.T. Lydall D. A domain of Rad9 specifically required for activation of Chk1 in budding yeast J. Cell Sci. 117 2004 601 608 14709724 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In budding yeast, Mec1 activates Rad53 and Chk1; in human cells, ATM activates Chk2 and ATR activates Chk1.

    “In budding yeast, Mec1 activates both Rad53 and Chk1 [26], while in human cells Chk2 is activated by ATM and Chk1 by ATR [27].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Sanchez Y. Bachant J. Control of the DNA damage checkpoint by Chk1 and Rad53 protein kinases through distinct mechanisms Science 286 1999 1166 1171 10550056 source

      Not checked in the free run.

    • cites [27] Bartek J. Lukas J. Chk1 and Chk2 kinases in checkpoint control and cancer Cancer Cell 3 2003 421 429 12781359 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Outside S phase and in non-cycling cells, UV lesions alone cannot activate the checkpoint; NER plays a major role in triggering the checkpoint response, though contrasting results exist.

    “Outside of S phase and in non cycling cells the situation is quite different. Recent analysis showed that UV lesions themselves cannot activate the checkpoint and NER plays a major role in triggering the checkpoint response, although contrasting results have also been reported [52–57].”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [52] 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.

    • cites [53] Bomgarden R.D. Lupardus P.J. Opposing effects of the UV lesion repair protein XPA and UV bypass polymerase eta on ATR checkpoint signaling EMBO J. 25 2006 2605 2614 16675950 PMC1478198 source

      Not checked in the free run.

    • cites [54] O’Driscoll M. Ruiz-Perez V.L. A splicing mutation affecting expression of ataxia–telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome Nat. Genet. 33 2003 497 501 12640452 source

      Not checked in the free run.

    • cites [55] Giannattasio M. Lazzaro F. 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 [56] Marini F. Nardo T. DNA nucleotide excision repair-dependent signaling to checkpoint activation Proc. Natl. Acad. Sci. U.S.A. 103 2006 17325 17330 17088560 PMC1859929 source

      Not checked in the free run.

    • cites [57] Marti T.M. Hefner E. 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. 2006 PMC1502549 16788066 source

      Not checked in the free run.

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

    Premisecitation

    Effector kinases phosphorylate many targets, including cell cycle machinery and proteins important for replication and repair.

    “Finally, effector kinases are responsible for the phosphorylation of a great number of targets, including cell cycle machinery factors and key proteins important for replication and repair [32,33].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [32] Smolka M.B. Albuquerque C.P. Proteome-wide identification of in vivo targets of DNA damage checkpoint kinases Proc. Natl. Acad. Sci. U.S.A. 104 2007 10364 10369 17563356 PMC1965519 source

      Not checked in the free run.

    • cites [33] Matsuoka S. Ballif B.A. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage Science 316 2007 1160 1166 17525332 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATR can also be recruited to DSBs, and this binding depends on ATM.

    “The situation is somewhat complicated by the finding that ATR can be also recruited to DSBs and this binding depends upon ATM [41,42].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [41] Jazayeri A. Falck J. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks Nat. Cell Biol. 8 2006 37 45 16327781 source

      Not checked in the free run.

    • cites [42] Adams K.E. Medhurst A.L. Recruitment of ATR to sites of ionising radiation-induced DNA damage requires ATM and components of the MRN protein complex Oncogene 25 2006 3894 3904 16474843 PMC1852851 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rad9 oligomerization is critical for scaffolding Rad53 binding, increasing local Rad53 concentration and stimulating autophosphorylation, leading to full Rad53 activation.

    “Oligomerization of Rad9 seems to be critical to provide a scaffold for Rad53 binding, leading to a local increase in Rad53 molecules and stimulating its auto-phosphorylation; this event is responsible for full Rad53 activation [28,29].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Sweeney F.D. Yang F. Saccharomyces cerevisiae Rad9 acts as a Mec1 adaptor to allow Rad53 activation Curr. Biol. 15 2005 1364 1375 16085488 source

      Not checked in the free run.

    • cites [29] Gilbert C.S. Green C.M. Lowndes N.F. Budding yeast Rad9 is an ATP-dependent Rad53 activating machine Mol. Cell 8 2001 129 136 11511366 source

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  • May combine two claims.

    Premisecitation

    Rad9 phosphorylation by the apical kinase recruits Rad53 to the damage site, allowing Mec1 to phosphorylate it.

    “The prototype of checkpoint mediators is S. cerevisiae Rad9, which, once phosphorylated by the apical kinase, recruits Rad53 at the damage site allowing its phosphorylation by Mec1.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [28] Sweeney F.D. Yang F. Saccharomyces cerevisiae Rad9 acts as a Mec1 adaptor to allow Rad53 activation Curr. Biol. 15 2005 1364 1375 16085488 source

      Not checked in the free run.

    • cites [29] Gilbert C.S. Green C.M. Lowndes N.F. Budding yeast Rad9 is an ATP-dependent Rad53 activating machine Mol. Cell 8 2001 129 136 11511366 source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    UV irradiation causes bulky lesions, mainly cyclobutane pyrimidine dimers and 6,4 photoproducts, that distort the DNA helix.

    “UV irradiation, which causes bulky lesions on DNA (mainly cyclobutane pyrimidine dimers (CPD) and 6,4 photoproducts (6-4PP)) responsible for inducing a distortion of the DNA helix [48]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [48] Friedberg E.C. Walker G.C. Siede W. DNA repair and mutagenesis 2006 ASM Press Washington, D.C.

      Not checked in the free run.

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

    Premisecitation

    The DNA damage checkpoint response is a signal transduction cascade based mainly on phosphorylation events.

    “The DNA damage checkpoint response consists of a signal transduction cascade mainly based on phosphorylation events; the mechanistic details of the pathway have been recently discussed elsewhere [15,16]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Putnam C.D. Jaehnig E.J. Kolodner R.D. Perspectives on the DNA damage and replication checkpoint responses in Saccharomyces cerevisiae DNA Repair (Amst) 8 2009 974 982 19477695 PMC2725198 source

      Not checked in the free run.

    • cites [16] Sancar A. Lindsey-Boltz L.A. 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.

  • May combine two claims.

    Interpretationcitation

    In human cells, MDC1, 53BP1, and BRCA1 are candidate functional Rad9 orthologues and may all be considered Rad9 orthologues.

    “In human cells, the identity of the functional Rad9 orthologue is still debated: multiple candidates exist – i.e., MDC1 (mediator of DNA-damage checkpoint 1), 53BP1 (p53-binding protein 1) and BRCA1 (breast cancer 1 early-onset) – all characterized by the presence of tandem BRCT (BRCA1 C-terminal repeat) domains. Since these three proteins are involved in checkpoint signal transduction and each of”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [31] FitzGerald J.E. Grenon M. Lowndes N.F. 53BP1: function and mechanisms of focal recruitment Biochem. Soc. Trans. 37 2009 897 904 19614615 source

      Not checked in the free run.

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

    Premisecitation

    Most reports agree that NER gap refilling is extremely rapid and tightly coordinated with incision.

    “but most reports seem to agree that the refilling is extremely rapid and tightly coordinated with the incision process [49,50]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [49] Staresincic L. Fagbemi A.F. Coordination of dual incision and repair synthesis in human nucleotide excision repair EMBO J. 28 2009 1111 1120 19279666 PMC2683701 source

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    • cites [50] Luijsterburg M.S. von Bornstaedt G. Stochastic and reversible assembly of a multiprotein DNA repair complex ensures accurate target site recognition and efficient repair J. Cell Biol. 189 2010 445 463 20439997 PMC2867314 source

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  • May combine two claims.

    Premisecitation

    ATRIP and Ddc2 directly bind RPA-covered ssDNA, while 9-1-1 loading requires an RFC-like complex that places it at the dsDNA/5′ ssDNA junction.

    “While ATRIP and Ddc2 directly bind RPA-covered ssDNA [44], loading of the 9-1-1 complex requires the activity of an RFC-like complex, that places it at the junction between dsDNA and 5′ ssDNA [45].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [44] Zou L. Elledge S.J. Sensing DNA damage through ATRIP recognition of RPA–ssDNA complexes Science 300 2003 1542 1548 12791985 source

      Not checked in the free run.

    • cites [45] Zou L. Liu D. Elledge S.J. Replication protein A-mediated recruitment and activation of Rad17 complexes Proc. Natl. Acad. Sci. U.S.A. 100 2003 13827 13832 14605214 PMC283506 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    NER lesion recognition depends on physical location: TC-NER acts on transcription-blocking lesions, and GG-NER handles the rest of the genome.

    “The lesion recognition mechanism of NER depends upon the physical location of the lesion, with TC-NER acting on lesions that block transcription, and GG-NER taking care of the rest of the genome [48].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [48] Friedberg E.C. Walker G.C. Siede W. DNA repair and mutagenesis 2006 ASM Press Washington, D.C.

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human cells, the 9-1-1 complex cannot directly activate ATR but recruits TopBP1, which stimulates ATR.

    “In human cells, the 9-1-1 complex is not able to directly activate ATR, but it is needed to recruit TopBP1 (the Dpb11 orthologue) which, in turn, stimulates ATR activity [24].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [24] Navadgi-Patil V.M. Burgers P.M. A tale of two tails: activation of DNA damage checkpoint kinase Mec1/ATR by the 9-1-1 clamp and by Dpb11/TopBP1 DNA Repair (Amst) 8 2009 996 1003 19464966 PMC2725207 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In budding yeast, Mec1 is the main checkpoint activator after all DNA lesions, while Tel1 is mainly devoted to telomere maintenance; Tel1's redundant checkpoint role appears only without Mec1.

    “This separation of tasks is not found in budding yeast, where Mec1 (the ATR homologue) is the main player of checkpoint activation after all kind of DNA lesions, while Tel1 (the ATM homologue) is especially devoted to telomere maintenance. The redundant role of Tel1 in the DNA damage checkpoint is uncovered only in the absence of Mec1 [15,43].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [15] Putnam C.D. Jaehnig E.J. Kolodner R.D. Perspectives on the DNA damage and replication checkpoint responses in Saccharomyces cerevisiae DNA Repair (Amst) 8 2009 974 982 19477695 PMC2725198 source

      Not checked in the free run.

    • cites [43] Morrow D.M. Tagle D.A. TEL1, an S. cerevisiae homolog of the human gene mutated in ataxia telangiectasia, is functionally related to the yeast checkpoint gene, MEC1 Cell 82 1995 831 840 7545545 source

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  • May combine two claims.

    Premisecitation

    In S. cerevisiae, Mec1 can be activated by Ddc1 and by Dpb11 recruited through Ddc1.

    “In S. cerevisiae the Mec1 apical kinase can be activated both by the Ddc1 subunit of the checkpoint clamp and by the adaptor protein Dpb11 which is recruited at the lesion through interaction with Ddc1 [19–23].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [19] Majka J. Niedziela-Majka A. Burgers P.M. The checkpoint clamp activates Mec1 kinase during initiation of the DNA damage checkpoint Mol. Cell 24 2006 891 901 17189191 PMC1850967 source

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    • cites [20] Wang H. Elledge S.J. Genetic and physical interactions between DPB11 and DDC1 in the yeast DNA damage response pathway Genetics 160 2002 1295 1304 11973288 PMC1462046 source

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    • cites [21] Puddu F. Granata M. Phosphorylation of the budding yeast 9-1-1 complex is required for Dpb11 function in the full activation of the UV-induced DNA damage checkpoint Mol. Cell. Biol. 28 2008 4782 4793 18541674 PMC2493362 source

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    • cites [22] Navadgi-Patil V.M. Burgers P.M. Yeast DNA replication protein Dpb11 activates the Mec1/ATR checkpoint kinase J. Biol. Chem. 283 2008 35853 35859 18922789 PMC2602893 source

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    • cites [23] Mordes D.A. Nam E.A. Cortez D. Dpb11 activates the Mec1-Ddc2 complex Proc. Natl. Acad. Sci. U.S.A. 105 2008 18730 18734 19028869 PMC2596233 source

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  • May combine two claims.

    Premisecitation

    Checkpoints actively stimulate repair processes and, in higher eukaryotes, trigger apoptosis when damage cannot be successfully dealt with.

    “The checkpoints also actively stimulate the repair processes [1–9] and, in higher eukaryotes, trigger the apoptotic response, if damage cannot be dealt with successfully [10–12].”
    Quote in the paperNot a substantial claim0 of 10 sources checked
    • cites [1] Zhao X. Rothstein R. The Dun1 checkpoint kinase phosphorylates and regulates the ribonucleotide reductase inhibitor Sml1 Proc. Natl. Acad. Sci. U.S.A. 99 2002 3746 3751 11904430 PMC122595 source

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    • cites [2] Yao R. Zhang Z. Subcellular localization of yeast ribonucleotide reductase regulated by the DNA replication and damage checkpoint pathways Proc. Natl. Acad. Sci. U.S.A. 100 2003 6628 6633 12732713 PMC164498 source

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    • cites [3] Bashkirov V.I. King J.S. DNA repair protein Rad55 is a terminal substrate of the DNA damage checkpoints Mol. Cell. Biol. 20 2000 4393 4404 10825202 PMC85806 source

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    • cites [4] Ahnesorg P. Jackson S.P. The non-homologous end-joining protein Nej1p is a target of the DNA damage checkpoint DNA Repair (Amst) 6 2007 190 201 17101301 PMC3338008 source

      Not checked in the free run.

    • cites [5] Flott S. Alabert C. Phosphorylation of Slx4 by Mec1 and Tel1 regulates the single-strand annealing mode of DNA repair in budding yeast Mol. Cell. Biol. 27 2007 6433 6445 17636031 PMC2099619 source

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    • cites [6] Morin I. Ngo H.P. Checkpoint-dependent phosphorylation of Exo1 modulates the DNA damage response EMBO J. 27 2008 2400 2410 18756267 PMC2532783 source

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    • cites [7] Chou W.C. Wang H.C. Chk2-dependent phosphorylation of XRCC1 in the DNA damage response promotes base excision repair EMBO J. 27 2008 3140 3150 18971944 PMC2599873 source

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    • cites [8] Al-Moghrabi N.M. Al-Sharif I.S. Aboussekhra A. The RAD9-dependent gene trans-activation is required for excision repair of active genes but not for repair of non-transcribed DNA Mutat. Res. 663 2009 60 68 19428371 source

      Not checked in the free run.

    • cites [9] Ciccia A. Elledge S.J. The DNA damage response: making it safe to play with knives Mol. Cell 40 2010 179 204 20965415 PMC2988877 source

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    • cites [10] Lowe S.W. Schmitt E.M. p53 is required for radiation-induced apoptosis in mouse thymocytes Nature 362 1993 847 849 8479522 source

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  • May combine two claims.

    Interpretationreasoning

    If repair synthesis is perturbed, Exo1 may process the NER gap, generating a long ssDNA region that recruits checkpoint factors and triggers signaling.

    “If for any reason the repair synthesis step is perturbed, Exo1 may have a kinetic opportunity to process the NER gap, generating a long ssDNA region, which recruits checkpoint factors and triggers the signaling cascade (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    DNA polymerase κ directly participates in NER repair synthesis in human cells, and loss of TLS activity greatly potentiates the checkpoint response to UV in yeast G1 cells, suggesting closely opposing UV lesions may be at least partly responsible for checkpoint activation.

    “Interestingly, it was recently shown that DNA polymerase κ directly participates to NER repair synthesis in human cells [70,71] and that loss of TLS activity greatly potentiates the checkpoint response to UV irradiation in yeast G1 cells [61], suggesting that closely opposing UV lesions may indeed be at least partly responsible for checkpoint activation.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [70] Ogi T. Lehmann A.R. The Y-family DNA polymerase kappa (pol kappa) functions in mammalian nucleotide-excision repair Nat. Cell Biol. 8 2006 640 642 16738703 source

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    • cites [71] Ogi T. Limsirichaikul S. Three DNA polymerases, recruited by different mechanisms, carry out NER repair synthesis in human cells Mol. Cell 37 2010 714 727 20227374 source

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    • cites [61] Giannattasio M. Follonier C. Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation Mol. Cell 40 2010 50 62 20932474 source

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    • Rests on an assumption: DNA polymerase δ or ε cannot replicate past a UV lesion in the template strand and stalls during NER repair synthesis.

  • May combine two claims.

    Premisecitation

    XPC cells defective in GG-NER show checkpoint failure, while Cockayne syndrome cells defective in TC-NER can activate the checkpoint, possibly via GG-NER.

    “Interestingly, while XPC cells, defective in GG-NER, exhibit a checkpoint failure, cells obtained from Cockayne syndrome patients, which are defective in TC-NER, are instead able to activate the checkpoint, possibly thanks to the activity of GG-NER.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [56] Marini F. Nardo T. DNA nucleotide excision repair-dependent signaling to checkpoint activation Proc. Natl. Acad. Sci. U.S.A. 103 2006 17325 17330 17088560 PMC1859929 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In cycling NER-deficient cells, UV irradiation would not cause G1 delay or G2/M arrest, and replication of the damaged template would accumulate ssDNA regions leading to Mec1 activation.

    “In cycling NER-deficient cells, UV irradiation would not cause a G1 delay or G2/M arrest and replication of the damaged template would lead to the accumulation of ssDNA regions resulting in Mec1 activation.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    A direct interaction between Rad14 and the 9-1-1 checkpoint complex was reported, but its physiological significance has not been fully addressed.

    “Furthermore, a direct interaction between Rad14 and the 9-1-1 checkpoint complex was reported, albeit its physiological significance has not been fully addressed.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [55] Giannattasio M. Lazzaro F. 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.

  • May combine two claims.

    Interpretationreasoning

    The model that gapped NER intermediates activate the checkpoint in UV-irradiated cells has problems: the gaps are very short (~30 nt), repair synthesis is very rapid so gaps are virtually absent, and it is unclear what advantage checkpoint activation would have once damage is practically repaired.

    “The model suggesting that gapped NER intermediates are responsible for checkpoint activation in UV-irradiated cells poses a few problems: (a) the gaps are very short (∼30 nt); (b) repair synthesis is very rapid, so the gaps are virtually absent; (c) it is not clear what would be the advantage of activating the checkpoint and arresting cell cycle progression, once the damage is practically repaired”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    This Exo1-dependent processing may occur at higher UV doses, when repair synthesis factors become limiting, or when the refilling polymerase encounters an insurmountable block.

    “This situation may arise, for example, at higher UV doses, in case repair synthesis factors become limiting or if the refilling polymerase encounters an insurmountable block.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationcitation

    In these conditions, repair may not be completed and ssDNA extension may both activate the checkpoint and channel the problematic lesion to another repair pathway such as recombination.

    “In these conditions, repair may not be completed and the extension of the ssDNA region may meet two purposes: activating the checkpoint response and channeling the problematic lesion to a different repair pathway (e.g., recombination) [66–68].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [66] Karras G.I. Jentsch S. The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase Cell 141 2010 255 267 20403322 source

      Not checked in the free run.

    • cites [67] Daigaku Y. Davies A.A. Ulrich H.D. Ubiquitin-dependent DNA damage bypass is separable from genome replication Nature 465 2010 951 955 20453836 PMC2888004 source

      Not checked in the free run.

    • cites [68] Stergiou L. Eberhard R. NER and HR pathways act sequentially to promote UV-C-induced germ cell apoptosis in Caenorhabditis elegans Cell Death Differ. 18 2011 897 906 21151025 PMC3131928 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    G1 synchronized yeast mutants lacking TLS polymerases are more sensitive to UV than asynchronous cultures, while TLS-proficient strains are not.

    “Moreover, a role for TLS in G1-irradiated cells is also supported by the finding that G1 synchronized cultures of yeast mutants lacking TLS polymerases are more sensitive to UV light than asynchronous cultures, while this is not the case for strains that are TLS proficient [61].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Giannattasio M. Follonier C. Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation Mol. Cell 40 2010 50 62 20932474 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In human XP cells, lack of NER-dependent processing prevents UV-induced checkpoint activity in non-cycling fibroblasts, and XP cells are deficient in both repair and G1/G2/M UV-induced checkpoint.

    “Extension of this kind of analysis to human cells derived from XP patients confirmed that lack of NER-dependent processing prevented UV-induced checkpoint activity in non cycling fibroblasts, revealing that XP cells are not only deficient in repairing UV lesions, but they are also deficient in the G1 and G2/M UV-induced checkpoint [56,57].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [56] Marini F. Nardo T. DNA nucleotide excision repair-dependent signaling to checkpoint activation Proc. Natl. Acad. Sci. U.S.A. 103 2006 17325 17330 17088560 PMC1859929 source

      Not checked in the free run.

    • cites [57] Marti T.M. Hefner E. 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. 2006 PMC1502549 16788066 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Blocked polymerases can leave the lesion and PCNA behind and re-initiate downstream via re-priming, generating numerous ssDNA gaps behind forks that likely cause strong Mec1 activation during S phase in UV-irradiated cells.

    “Blocked polymerase can leave the lesion and PCNA behind and re-initiate downstream of the lesion via a re-priming mechanism, generating numerous ssDNA gaps behind the forks, which are likely responsible for the strong activation of Mec1 during S phase in UV-irradiated cells [51,82–85].”
    Quote in the paperSubstantial claim0 of 5 sources checked
    • cites [51] Lopes M. Foiani M. Sogo J.M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions Mol. Cell 21 2006 15 27 16387650 source

      Not checked in the free run.

    • cites [82] Rupp W.D. Howard-Flanders P. Discontinuities in the DNA synthesized in an excision-defective strain of Escherichia coli following ultraviolet irradiation J. Mol. Biol. 31 1968 291 304 4865486 source

      Not checked in the free run.

    • cites [83] Lehmann A.R. Post-replication repair of DNA in ultraviolet-irradiated mammalian cells. No gaps in DNA synthesized late after ultraviolet irradiation Eur. J. Biochem. 31 1972 438 445 4675366 source

      Not checked in the free run.

    • cites [84] di Caprio L. Cox B.S. DNA synthesis in UV-irradiated yeast Mutat. Res. 82 1981 69 85 7022172 source

      Not checked in the free run.

    • cites [85] Prakash L. Characterization of postreplication repair in Saccharomyces cerevisiae and effects of rad6, rad18, rev3 and rad52 mutations Mol. Gen. Genet. 184 1981 471 478 7038396 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In non-cycling cells, any NER mutation affecting incision causes deficient checkpoint activity, showing that UV lesions alone are not sufficient to trigger the apical checkpoint kinase and that their processing by repair is necessary for recruiting Mec1/Ddc2 and 9-1-1 and for a prompt checkpoint response.

    “This work also showed that, in non cycling cells, any NER mutation affecting the incision event caused a deficient checkpoint activity, demonstrating that UV lesions per se are not sufficient to trigger the apical checkpoint kinase, and that their processing by a repair mechanism is necessary for recruiting the Mec1/Ddc2 and the 9-1-1 complexes to damaged chromosomes and for a prompt checkpoint”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Giannattasio M. Lazzaro F. 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.

  • May combine two claims.

    Premisecitation

    UV-induced photoproducts and DSBs are processed by different repair pathways and trigger signaling by distinct apical kinases, but eventually generate the same epigenetic mark involving H2A ubiquitination.

    “although UV-induced photoproducts and DSBs are processed by different DNA repair pathways and trigger signaling responses controlled by distinct apical kinases (see above) they eventually generate the same epigenetic mark involving H2A ubiquitination [59].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [59] Marteijn J.A. Bekker-Jensen S. Nucleotide excision repair-induced H2A ubiquitination is dependent on MDC1 and RNF8 and reveals a universal DNA damage response J. Cell Biol. 186 2009 835 847 19797077 PMC2753161 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UV irradiation causes accumulation of long ssDNA regions in yeast chromosomes that depend on NER and Exo1 and correlate with Mec1 kinase activation.

    “This work shows that UV irradiation causes the accumulation, in yeast chromosomes, of long ssDNA regions that are dependent upon NER and Exo1 and correlate with Mec1 kinase activation.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [60] Nakada D. Hirano Y. Sugimoto K. Requirement of the Mre11 complex and exonuclease 1 for activation of the Mec1 signaling pathway Mol. Cell. Biol. 24 2004 10016 10025 15509802 PMC525484 source

      Not checked in the free run.

    • cites [61] Giannattasio M. Follonier C. Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation Mol. Cell 40 2010 50 62 20932474 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    UV irradiation in G1 of cycling rad14Δ cells causes strong arrest at the beginning of S phase, accompanied by accumulation of replication-dependent ssDNA regions.

    “Such results are also consistent with the finding that UV irradiation in G1 of a cycling rad14Δ strain results in a strong arrest at the beginning of S phase [58], accompanied by the accumulation of replication-dependent ssDNA regions [51].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [58] Neecke H. Lucchini G. Longhese M.P. Cell cycle progression in the presence of irreparable DNA damage is controlled by a Mec1- and Rad53-dependent checkpoint in budding yeast EMBO J. 18 1999 4485 4497 10449414 PMC1171523 source

      Not checked in the free run.

    • cites [51] Lopes M. Foiani M. Sogo J.M. Multiple mechanisms control chromosome integrity after replication fork uncoupling and restart at irreparable UV lesions Mol. Cell 21 2006 15 27 16387650 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In NER-deficient cells, failure to remove lesions and to activate the G1 checkpoint allows many lesions to enter S phase.

    “As mentioned above, in NER deficient cells, the lack of lesion removal coupled to the failure to activate the G1 DNA damage checkpoint in response to UV irradiation allows a large amount of DNA lesions to go into S phase.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The frequency of large ssDNA gaps is much lower than the expected frequency of UV damages, suggesting only a minor fraction of lesions undergo Exo1-dependent processing.

    “The frequency of these large ssDNA gaps is much lower than the expected frequency of UV damages, suggesting that only a minor fraction of lesions undergo Exo1-dependent processing.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    The ~30 nt NER gaps can be either refilled by DNA polymerases or extended by Exo1; because polymerases refill much faster than Exo1 excises, most UV lesions are normally rapidly repaired by NER.

    “These results suggest that the ∼30 nt long ssDNA gaps produced by NER can be refilled by DNA polymerases or extended by Exo1; given that polymerases refill a DNA gap at a rate of about 3700 nt/min and Exo1 excises DNA at 160 nt/min, most UV lesions are normally rapidly repaired by NER.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NER plays a role in ATM activation after cisplatin treatment; ATM physically interacts with NER factors and this association is required for ATM recruitment to DNA.

    “In addition, a role for NER in the activation of ATM after cisplatin treatment was discovered. Immunoprecipitation experiments revealed a physical interaction between ATM and NER factors and this association is required for ATM recruitment to DNA [94] (Fig. 3).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [94] Colton S.L. Xu X.S. 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.

    Premisecitation

    S phase can be completed without PRR, but gapped replicated DNA must be refilled by PRR in G2 for cell survival.

    “In fact, S phase can be completed in the absence of PRR, but the gapped replicated DNA needs to be refilled by PRR in G2 in order to warrant cell survival [66,67].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [66] Karras G.I. Jentsch S. The RAD6 DNA damage tolerance pathway operates uncoupled from the replication fork and is functional beyond S phase Cell 141 2010 255 267 20403322 source

      Not checked in the free run.

    • cites [67] Daigaku Y. Davies A.A. Ulrich H.D. Ubiquitin-dependent DNA damage bypass is separable from genome replication Nature 465 2010 951 955 20453836 PMC2888004 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Inhibition of ATR specifically blocks NER during S phase, while repair rate in G1 and G2/M cells is unaffected.

    “In particular, ATR inhibition was shown to specifically abrogate NER in S-phase, while the repair rate was unaffected in G1 and G2/M cells [89].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [89] Auclair Y. Rouget R. 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 2008 17896 17901 19004803 PMC2584713 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Claspin knockdown affects recruitment of DDB2 to damage sites and its subsequent ubiquitin-mediated degradation.

    “Claspin knockdown affects DDB2 recruitment at damage sites and its subsequent ubiquitin-mediated degradation; in agreement with this observation, it has been shown that Claspin and DDB2 physically interact and their association is greatly enhanced upon UV irradiation [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Praetorius-Ibba M. Wang Q.E. Role of Claspin in regulation of nucleotide excision repair factor DDB2 DNA Repair (Amst) 6 2007 578 587 17196446 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Claspin regulates the DDB2 subunit of the UV-DDB factor, which acts in early steps of GG-NER.

    “Another report revealed a role for the replication checkpoint mediator Claspin in regulating the DDB2 subunit of the UV-DDB factor, which is involved in the initial steps of GG-NER [103].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [103] Praetorius-Ibba M. Wang Q.E. Role of Claspin in regulation of nucleotide excision repair factor DDB2 DNA Repair (Amst) 6 2007 578 587 17196446 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    A NER-independent mechanism for activating checkpoint kinases seems to exist in non-cycling cells; NER-deficient yeast blocked in G1 and UV irradiated show delayed Mec1-dependent pathway activation.

    “Interestingly, a NER-independent mechanism for activating checkpoint kinases seems to exist in non cycling cells. If NER-deficient yeast cells are blocked in the G1 phase of the cell cycle, UV irradiated and held in non dividing conditions indefinitely, a delayed activation of the Mec1-dependent pathway has been reported [95,96].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [95] 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.

    • cites [96] Giannattasio M. Lazzaro F. DNA decay and limited Rad53 activation after liquid holding of UV-treated nucleotide excision repair deficient S. cerevisiae cells DNA Repair (Amst) 3 2004 1591 1599 15474420 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In S. cerevisiae, Rad14 physically interacts with Ddc1 and Mec3, and association of Ddc1/Ddc2 with UV-damaged chromosomes is lost in rad14Δ, suggesting 9-1-1 may be initially recruited by Rad14.

    “In S. cerevisiae, a physical interaction was identified between Rad14 and both Ddc1 and Mec3, two subunits of the 9-1-1 checkpoint complex. Although the physiological relevance of this interaction has not been directly investigated further, association of Ddc1 and Ddc2 to UV-damaged chromosomes is lost in a rad14Δ strain, suggesting that the 9-1-1 complex may be initially recruited at the sites of”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [55] Giannattasio M. Lazzaro F. 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.

  • May combine two claims.

    Premisecitation

    In mammalian cells, NER also acts in S phase, where GG-NER is enhanced and stimulated by active ATR.

    “In mammalian cells the situation is more complex, because NER acts also in S phase, where GG-NER is enhanced [88] and is stimulated by active ATR [89,90].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [88] Gospodinov A. Anachkova B. Cells synchronized in S phase show increased rate of repair of UV damaged plasmids FEBS Lett. 572 2004 99 102 15304331 source

      Not checked in the free run.

    • cites [89] Auclair Y. Rouget R. 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 2008 17896 17901 19004803 PMC2584713 source

      Not checked in the free run.

    • cites [90] Auclair Y. Rouget R. Drobetsky E.A. ATR kinase as master regulator of nucleotide excision repair during S phase of the cell cycle Cell Cycle 8 2009 1865 1871 19440044 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    An active checkpoint leads to Rev1 phosphorylation, possibly increasing TLS activity and reducing RPA-covered ssDNA, promoting checkpoint switch-off.

    “An active checkpoint leads to Rev1 phosphorylation [86,87], possibly increasing TLS activity and progressively reducing the amount of RPA-covered ssDNA, thus promoting the switch off of the checkpoint itself.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [86] Pagès V. Santa Maria S.R. Role of DNA damage-induced replication checkpoint in promoting lesion bypass by translesion synthesis in yeast Genes Dev. 23 2009 1438 1449 19528320 PMC2701570 source

      Not checked in the free run.

    • cites [87] Sabbioneda S. Bortolomai I. Yeast Rev1 is cell cycle regulated, phosphorylated in response to DNA damage and its binding to chromosomes is dependent upon MEC1 DNA Repair (Amst) 6 2007 121 127 17035102 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    When lesion levels are low, ssDNA gaps build up and turn on checkpoint kinases near the end of S phase.

    “Since the region hosting a polymerase-blocking lesion can be almost completely replicated by an incoming fork starting from an adjacent origin, at low levels of lesions the gaps will accumulate and activate the checkpoint kinases toward the end of S phase.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: An adjacent origin's fork can replicate nearly all of a region with a polymerase-blocking lesion.
    • Rests on an assumption: Replicative polymerases encounter UV lesions, restart synthesis past them, and leave ssDNA gaps.

  • May combine two claims.

    Premisenone given

    XPA nuclear import and stable accumulation at nuclear foci after UV irradiation depend on ATR, and ATR seems responsible for XPA phosphorylation after UV.

    “It has been found that XPA nuclear import and its stable accumulation at nuclear foci after UV irradiation is dependent upon ATR. ATR also seems to be responsible for XPA phosphorylation after UV radiations,”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationreasoning

    With low UV-induced lesions, NER is very efficient and rapidly repairs most lesions, so neither G1 nor G2 checkpoints are activated.

    “With low levels of UV-induced lesions the NER mechanism is very efficient and rapidly takes care of most lesions, so that neither the G1 or the G2 checkpoints are activated.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Once the checkpoint is active, PRR refills the gaps and the lesions are removed from chromosomes.

    “This event has a clear relevance since checkpoint mutants will die in this situation, and only after checkpoint activation the gaps are refilled by PRR and the lesions are actually removed from the chromosomes [61].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [61] Giannattasio M. Follonier C. Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation Mol. Cell 40 2010 50 62 20932474 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The few lesions encountered by replicating polymerases block the fork and trigger a checkpoint response, detectable in late S phase when most replicons have completed duplication and leftover ssDNA gaps need refilling.

    “The few lesions that are encountered by replicating polymerases in these conditions, on the other hand, block the replication fork and trigger a checkpoint response; this response may be detected in late S phase, when most replicons have completed duplication and the left-over ssDNA gaps need to be refilled (Fig. 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    NER-deficient (rad14Δ) and checkpoint-deficient (mec1Δ) cells are not particularly sensitive to CLUV, unlike rad18Δ and rad5Δ PRR-deficient cells, which irreversibly activate Mec1 checkpoint and die in G2.

    “Indeed, NER deficient cells (rad14Δ) and DNA damage checkpoint deficient cells (mec1Δ) are not particularly sensitive to the CLUV treatment, contrary to the rad18Δ and rad5Δ cells, deficient in PRR [65], which irreversibly activate Mec1 DNA damage checkpoint and die in the G2 phase.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [65] Hishida T. Kubota Y. RAD6-RAD18-RAD5-pathway-dependent tolerance to chronic low-dose ultraviolet light Nature 457 2008 612 615 19079240 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CSB, the human orthologue of Rad26, was identified in a screen for putative ATM/ATR substrates, pointing to conservation of this regulatory mechanism.

    “Notably, CSB (the human orthologue of Rad26) was identified in a screen for putative ATM/ATR substrates [33], pointing to a conservation of this regulatory mechanism through evolution.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Matsuoka S. Ballif B.A. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage Science 316 2007 1160 1166 17525332 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Rad26, critical for TC-NER, is a direct target of Mec1 kinase, and its phosphorylation enhances TC-NER, possibly by stimulating ATPase activity or modulating interactions with other TC-NER proteins.

    “Along similar lines, Rad26, a NER factor critical for TC-NER, is a direct target of Mec1 kinase and its phosphorylation enhances TC-NER, possibly by stimulating its ATPase activity or by modulating its interaction with other TC-NER proteins [99].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [99] Taschner M. Harreman M. A role for checkpoint kinase-dependent Rad26 phosphorylation in transcription-coupled DNA repair in Saccharomyces cerevisiae Mol. Cell. Biol. 30 2010 436 446 19901073 PMC2798469 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Repair factors help recruit checkpoint proteins to damage sites and trigger the checkpoint cascade by converting primary lesions to RPA-covered ssDNA.

    “On one side, repair factors help to recruit checkpoint proteins at the damage sites onto DNA and, by modifying the primary lesions to RPA-covered ssDNA, trigger the checkpoint cascade; on the other side, once activated the checkpoint pathway stimulates the repair process mainly through direct protein–protein interactions or post-translational modifications.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Rad9 does not seem required for repair of non-transcribed regions, suggesting it acts only when repair is coupled to transcription.

    “Rad9 does not seem to be required for the repair of non-transcribed regions, suggesting that it is acting only when repair is coupled to transcription [8].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [8] Al-Moghrabi N.M. Al-Sharif I.S. Aboussekhra A. The RAD9-dependent gene trans-activation is required for excision repair of active genes but not for repair of non-transcribed DNA Mutat. Res. 663 2009 60 68 19428371 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    In human cells, both ATR-dependent checkpoint and TLS influence S phase-specific GG-NER; defects in ATR or pol η may cause persistent ssDNA gaps opposite template lesions and inhibit GG-NER excision.

    “Thus, in human cells both ATR-dependent DNA damage checkpoint and TLS influence S phase-specific GG-NER: defects in ATR or pol η may cause the abnormal persistence of ssDNA gaps opposite a template lesion and this would inhibit DNA adducts excision by GG-NER.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    ATR-deficient Seckel syndrome fibroblasts show attenuation of S phase-specific GG-NER, and a similar effect occurs in XPV skin fibroblasts deficient in pol η.

    “Indeed, ATR-deficient Seckel syndrome fibroblasts exhibit attenuation of S phase specific GG-NER and a similar effect has been detected in XPV skin fibroblasts, deficient in pol η [91].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [91] Auclair Y. Rouget R. Requirement for functional DNA polymerase eta in genome-wide repair of UV-induced DNA damage during S phase DNA Repair (Amst) 9 2010 754 764 20457011 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Claspin and DDB2 physically interact, and their association increases greatly after UV irradiation.

    “Claspin knockdown affects DDB2 recruitment at damage sites and its subsequent ubiquitin-mediated degradation; in agreement with this observation, it has been shown that Claspin and DDB2 physically interact and their association is greatly enhanced upon UV irradiation [103].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [103] Praetorius-Ibba M. Wang Q.E. Role of Claspin in regulation of nucleotide excision repair factor DDB2 DNA Repair (Amst) 6 2007 578 587 17196446 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CPD and 6-4PP are key drivers of sunlight-induced mutagenesis and skin cancer.

    “NER is the most versatile repair system and eliminates a wide repertoire of DNA lesions, among which are UV-induced CPD and 6-4PP, that represent the main determinants in solar mutagenesis and skin cancer [105,106].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [105] Brash D.E. Rudolph J.A. A role for sunlight in skin-cancer – UV-induced p53 mutations in squamous-cell carcinoma Proc. Natl. Acad. Sci. U.S.A. 88 1991 10124 10128 1946433 PMC52880 source

      Not checked in the free run.

    • cites [106] Tornaletti S. Pfeifer G.P. Slow repair of pyrimidine dimers at p53 mutation hotspots in skin-cancer Science 263 1994 1436 1438 8128225 source

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S2 (checkable), S3 (load-bearing).

    Interpretationreasoning

    These findings may matter beyond UV exposure-related problems.

    “The importance of the findings summarized here may thus expand further than the problems related to exposure to UV light.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Under chronic low UV in yeast, NER is dispensable, as NER-deficient cells also show no sensitivity.

    “Even more surprisingly, NER is not important in these conditions, since NER-deficient cells are also not sensitive to CLUV.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [62] Tran P.T. Erdeniz N. EXO1-A multi-tasking eukaryotic nuclease DNA Repair (Amst) 3 2004 1549 1559 15474417 source

      Not checked in the free run.

63 of 63

  • The paper relies on this without support.

    DNA polymerase δ or ε cannot replicate past a UV lesion in the template strand and stalls during NER repair synthesis.

    “DNA polymerase δ or ɛ, which normally take care of repair synthesis, cannot replicate past the template lesion and stall, strongly resembling a blocked replication fork.”

  • The paper relies on this without support.

    The frequency of closely opposing UV lesions increases with the square of the UV dose.

    “Probability calculations would predict that the frequency of closely opposing lesions increases with the square of the UV dose and the chance of generating such situation in a yeast chromosome is expected to be very low.”

  • The paper relies on this without support.

    Chronic low UV is taken to be the closest mimic of sunlight.

    “What is surprising is what happens with chronic low UV doses (CLUV), which are supposed to best mimic sunlight exposure.”

  • The paper relies on this without support.

    XP patients lack NER and are markedly sun-sensitive.

    “The possibility to extend these findings beyond yeast cells remains to be determined, indeed they seem to contrast with the situation observed in XP patients, who are deficient in NER and clearly hypersensitive to sunlight.”

  • The paper relies on this without support.

    An adjacent origin's fork can replicate nearly all of a region with a polymerase-blocking lesion.

    “Since the region hosting a polymerase-blocking lesion can be almost completely replicated by an incoming fork starting from an adjacent origin, at low levels of lesions the gaps will accumulate and activate the checkpoint kinases toward the end of S phase.”

  • The paper relies on this without support.

    Replicative polymerases encounter UV lesions, restart synthesis past them, and leave ssDNA gaps.

    “When these damage-containing chromosomes are replicated, though, the DNA polymerases scanning the genome will eventually detect them, and re-initiate DNA synthesis further downstream leaving behind ssDNA gaps.”
6 of 6

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3 of the 111 references couldn’t be matched to a known paper.

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Authors
Novarina, D., Amara, F., Lazzaro, F., Plevani, P., & Muzi-Falconi, M.
Affiliations
University of Milan (IT)
Corresponding author
  • Plevani, Paolo
  • Muzi-Falconi, Marco
ORCID
Venue
DNA Repair
Publisher
Elsevier BV
Published
2011-07
Volume
10
Issue
7
Pages
751-759
ISSN
  • 1568-7856 (ISSN-L)
  • 1568-7864
DOI
10.1016/j.dnarep.2011.04.030
PMC
PMC3171152
OpenAlex
W2063623284
Cited by
43
References
111
Citations by year
2024: 2 · 2023: 3 · 2022: 2 · 2021: 1 · 2020: 1 · 2019: 5 · 2018: 1 · 2017: 2 · 2016: 4 · 2015: 8 · 2014: 7 · 2013: 6 · 2012: 1
FWCI
0.41
Type
journal article
Language
en
Open access
Licence
www.elsevier.com/tdm/userlicense/1.0/ (tdm)
Locations
  • DNA repair (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Keywords
UV-induced DNA damage, DNA damage checkpoint, nucleotide excision repair, checkpoint kinase, S phase, DNA replication, bulky DNA lesions, DNA repair intermediates
MeSH terms
DNA, DNA Damage, DNA Repair, DNA Replication, Humans, Models, Molecular, Phosphorylation, Protein Processing, Post-Translational, Ultraviolet Rays, S Phase, DNA Repair Enzymes

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 ›

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