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Cited by 247DNA Repair MechanismsRedox biology and oxidative stressEffects of Radiation Exposure

Functional interplay between ATM/ATR-mediated DNA damage response and DNA repair pathways in oxidative stress

Open access
Yan, Shan, Sorrell, Melanie, Berman, Zachary·2014·Cellular and Molecular Life Sciences
DOI 10.1007/s00018-014-1666-4PMC PMC4176976
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Abstract

To maintain genome stability, cells have evolved various DNA repair pathways to deal with oxidative DNA damage. DNA damage response (DDR) pathways, including ATM-Chk2 and ATR-Chk1 checkpoints, are also activated in oxidative stress to coordinate DNA repair, cell cycle progression, transcription, apoptosis, and senescence. Several studies demonstrate that DDR pathways can regulate DNA repair pathways. On the other hand, accumulating evidence suggests that DNA repair pathways may modulate DDR pathway activation as well. In this review, we summarize our current understanding of how various DNA repair and DDR pathways are activated in response to oxidative DNA damage primarily from studies in eukaryotes. In particular, we analyze the functional interplay between DNA repair and DDR pathways in oxidative stress. A better understanding of cellular response to oxidative stress may provide novel avenues of treating human diseases, such as cancer and neurodegenerative disorders.

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Written from the paper’s full text.

TL;DR

This review summarizes how oxidative stress activates ATM-Chk2 and ATR-Chk1 DNA damage response (DDR) pathways and how these pathways functionally interact with DNA repair pathways such as BER/SSBR, NER, MMR, HR, and NHEJ. It argues that DDR and DNA repair are integrated networks in oxidative stress, with unresolved questions about crosstalk and disease relevance.

Key findings

  • Oxidative stress is estimated to induce approximately 10,000 DNA alterations per cell per day, and can generate base damage, AP sites, SSBs, DSBs, crosslinks, stalled replication forks, and oxidatively-generated clustered DNA lesions.
  • ATM-Chk2 is activated primarily by DSBs, but oxidative stress can also activate ATM, as shown by hydrogen peroxide-induced ATM autophosphorylation at Serine 1981, p53 phosphorylation at Serine 15, and Chk2 phosphorylation at Threonine 68, even without H2AX phosphorylation at Serine 139.
  • ATR-Chk1 is activated by replication stress and other damage; hyperoxia (95% oxygen versus normal 21% oxygen) induced ATR-dependent but ATM-independent Chk1 phosphorylation at Serine 345 and p53 phosphorylation in A549 cells.
  • DDR pathways regulate DNA repair, and DNA repair proteins also regulate DDR: for example, Chk2-dependent XRCC1 phosphorylation at Threonine 284 promotes XRCC1 recruitment, ATM-dependent TDP1 phosphorylation at Serine 81 facilitates TDP1 recruitment, and APE2 is required for ATR-Chk1 checkpoint activation in oxidative stress.

Methods

  • Design: narrative review of current understanding of oxidative stress-induced DNA damage, DDR pathways, and DNA repair pathways, primarily from studies in eukaryotes.
  • Data or sample: no primary experimental sample; the paper synthesizes published literature and cites studies in human cell lines, Xenopus egg extracts, yeast, and other model systems.
  • Main analysis: conceptual synthesis of ATM-Chk2 and ATR-Chk1 activation mechanisms, crosstalk between them, and functional connections with BER/SSBR, NER, MMR, HR, and NHEJ, supported by schematic figures.

Limitations

  • Stated in the paper: it remains challenging to quantitatively measure oxidatively-generated DNA damage without measuring intermediate repair products; it is elusive how accumulation of unrepaired oxidative DNA damage leads to cancer and neurodegenerative diseases; more investigation is needed on interplay between ATM/ATR-mediated DDR and DNA damage tolerance pathways; and it is unclear how ATM-Chk2 and ATR-Chk1 crosstalk in oxidative stress.
  • Evident from the text: this is a narrative review rather than a systematic review or meta-analysis, and it focuses on higher eukaryotic model organisms.
  • Evident from the text: many mechanistic details remain unresolved, including exactly how DDR pathways regulate DNA repair in oxidative stress, whether ATR or Chk1 kinase activity directly regulates BER, and how the 9-1-1 complex stimulates BER at nearly all steps.

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Integrity signals

Registry

Crossref · 10.1007/s00018-014-1666-4

Cites

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Statistics

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Claims the paper makes

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  • Premisecitation

    In normal conditions ATM is inactive as a dimer or higher-order oligomer, with its kinase domain blocked by a region around serine 1981.

    “Under normal conditions, ATM is inactive in a dimer or higher-order oligomer status, when its kinase domain is bound by a region surrounding a critical Serine 1981 and prevented from activation.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Bakkenist CJ, Kastan MB (2004) Initiating cellular stress responses. Cell 118(1):9–17. doi: 10.1016/j.cell.2004.06.023 source

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    • cites [51] Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506. doi: 10.1038/nature01368 source

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  • Premisecitation

    In vitro reconstitution showed that the MRN complex stimulates ATM kinase activity toward substrates including Chk2, p53, and histone H2AX.

    “An in vitro reconstitution analysis further revealed that the MRN complex stimulates ATM kinase activity toward its substrates such as Chk2, p53, and histone H2AX [57]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [57] Lee JH, Paull TT (2004) Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304(5667):93–96. doi: 10.1126/science.1091496 source

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  • Premisecitation

    In an ischemic retinopathy model, ROS-induced ATM activation promotes endothelial proliferation by suppressing ROS accumulation as a feedback mechanism.

    “In an ischemic retinopathy model, ATM activation by ROS promotes endothelial proliferation by suppressing ROS accumulation as a feedback mechanism [68].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [68] Okuno Y, Nakamura-Ishizu A, Otsu K, Suda T, Kubota Y (2012) Pathological neoangiogenesis depends on oxidative stress regulation by ATM. Nat Med 18(8):1208–1216. doi: 10.1038/nm.2846 source

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  • Premisecitation

    In response to double-strand breaks, ATM autophosphorylates serine 1981, which causes dimer dissociation into monomers and full ATM activation.

    “However, in response to DSBs, ATM auto-phosphorylates Serine 1981, leading to dimer dissociation into a monomer and the full activation of ATM [50, 51].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [50] Bakkenist CJ, Kastan MB (2004) Initiating cellular stress responses. Cell 118(1):9–17. doi: 10.1016/j.cell.2004.06.023 source

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    • cites [51] Bakkenist CJ, Kastan MB (2003) DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 421(6922):499–506. doi: 10.1038/nature01368 source

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  • Premisecitation

    Oxidative stress caused by hypoxia-reoxygenation in endothelial cells can induce chromosomal aberrations such as dicentric chromosomes and micronuclei.

    “Oxidative stress by hypoxia-reoxygenation in endothelial cells may induce more profound damage, such as chromosomal aberrations (e.g., dicentric chromosomes) and micronuclei [26].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [26] Bresgen N, Karlhuber G, Krizbai I, Bauer H, Bauer HC, Eckl PM (2003) Oxidative stress in cultured cerebral endothelial cells induces chromosomal aberrations, micronuclei, and apoptosis. J Neurosci Res 72(3):327–333. doi: 10.1002/jnr.10582 source

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    Premisecitation

    Oxidative stress can produce many forms of DNA damage or replication stress, including base and sugar damage, AP sites, single-strand breaks, double-strand breaks, tandem base modifications, interstrand crosslinks, protein-DNA crosslinks, mismatched pairs with damaged bases, stalled replication forks, and oxidatively generated clustered lesions.

    “Oxidative stress can induce a variety of different types of DNA damage or replication stress, such as base (purine and pyrimidine) damage, sugar moiety damage, Apurinic/apyrimidinic (AP) sites, DNA single-strand breaks (SSBs), DNA double-strand breaks (DSBs), tandem base modifications (e.g., DNA intrastrand crosslink), DNA interstrand crosslinks, protein–DNA crosslinks, mismatched pairs with dam”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [17] Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715 source

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    • cites [18] Friedberg EC (2003) DNA damage and repair. Nature 421(6921):436–440. doi: 10.1038/nature01408 source

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    • cites [19] Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204. doi: 10.1016/j.molcel.2010.09.019 source

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    • cites [20] Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361(15):1475–1485. doi: 10.1056/NEJMra0804615 source

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    • cites [21] Cadet J, Ravanat JL, TavernaPorro M, Menoni H, Angelov D (2012) Oxidatively generated complex DNA damage: tandem and clustered lesions. Cancer Lett 327(1–2):5–15. doi: 10.1016/j.canlet.2012.04.005 source

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    Premisecitation

    Oxidative stress is estimated to cause roughly 10,000 DNA alterations per cell each day, accounting for a major share of endogenous DNA damage.

    “It is estimated that oxidative stress may induce approximately 10,000 DNA alterations per cell per day, representing a major portion of endogenous DNA damage [17–20].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [17] Lindahl T (1993) Instability and decay of the primary structure of DNA. Nature 362:709–715 source

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    • cites [18] Friedberg EC (2003) DNA damage and repair. Nature 421(6921):436–440. doi: 10.1038/nature01408 source

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    • cites [19] Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204. doi: 10.1016/j.molcel.2010.09.019 source

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    • cites [20] Hoeijmakers JH (2009) DNA damage, aging, and cancer. N Engl J Med 361(15):1475–1485. doi: 10.1056/NEJMra0804615 source

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    Premisecitation

    Hydrogen peroxide treatment of primary neuron cells triggers γ-H2AX, indicating double-strand break generation and ATM activation.

    “Hydrogen peroxide treatment in primary neuron cells triggers γ-H2AX, indicating DSB generation and ATM activation [69].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [69] Singh S, Englander EW (2012) Nuclear depletion of apurinic/apyrimidinic endonuclease 1 (Ape1/Ref-1) is an indicator of energy disruption in neurons. Free Radic Biol Med 53(9):1782–1790. doi: 10.1016/j.freeradbiomed.2012.07.025 source

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    Premisecitation

    Histone H2AX is phosphorylated at serine 139 by ATM to form γ-H2AX, which prevents double-strand breaks from being processed into chromosomal translocations.

    “As an ATM substrate, histone H2AX is phosphorylated at Serine 139, which is referred to γ-H2AX and prevents DSBs from processing into chromosomal translocations [58, 59].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [58] Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM (1998) DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 273(10):5858–5868 source

      Not checked in the free run.

    • cites [59] Franco S, Gostissa M, Zha S, Lombard DB, Murphy MM, Zarrin AA, Yan C, Tepsuporn S, Morales JC, Adams MM, Lou Z, Bassing CH, Manis JP, Chen J, Carpenter PB, Alt FW (2006) H2AX prevents DNA breaks from progressing to chromosome breaks and translocations. Mol Cell 21(2):201–214. doi: 10.1016/j.molcel.2006.01.005 source

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    Premisecitation

    The MRN complex is involved in ataxia-telangiectasia-like disease and Nijmegen breakage syndrome and is required for ATM activation in the double-strand break response.

    “The MRN complex (Mre11-Rad50-Nbs1) is involved in ataxia-telangiectasia like disease and Nijmegen breakage syndrome and is required for ATM activation in DSB response [52–54].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [52] Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y (2003) Requirement of the MRN complex for ATM activation by DNA damage. EMBO J 22(20):5612–5621. doi: 10.1093/emboj/cdg541 source

      Not checked in the free run.

    • cites [53] van den Bosch M, Bree RT, Lowndes NF (2003) The MRN complex: coordinating and mediating the response to broken chromosomes. EMBO Rep 4(9):844–849. doi: 10.1038/sj.embor.embor925 source

      Not checked in the free run.

    • cites [54] Costanzo V, Paull T, Gottesman M, Gautier J (2004) Mre11 assembles linear DNA fragments into DNA damage signaling complexes. PLoS Biol 2(5):E110. doi: 10.1371/journal.pbio.0020110 source

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    Premisecitation

    ATM is the gene defective in ataxia-telangiectasia, an autosomal recessive disorder with early-onset progressive cerebellar ataxia, oculocutaneous telangiectasia, and susceptibility to lymphoid tumors.

    “ATM is a defective gene in Ataxia-telangiectasia (A-T), an autosomal recessive disorder with early onset progressive cerebellar ataxia, oculocutaneous telangiectasia, and lymphoid tumor susceptibility [48, 49].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [48] Lavin MF (2008) Ataxia-telangiectasia: from a rare disorder to a paradigm for cell signalling and cancer. Nat Rev Mol Cell Biol 9(10):759–769. doi: 10.1038/nrm2514 source

      Not checked in the free run.

    • cites [49] Savitsky K, Bar-Shira A, Gilad S, Rotman G, Ziv Y, Vanagaite L, Tagle DA, Smith S, Uziel T, Sfez S, Ashkenazi M, Pecker I, Frydman M, Harnik R, Patanjali SR, Simmons A, Clines GA, Sartiel A, Gatti RA, Chessa L, Sanal O, Lavin MF, Jaspers NG, Taylor AM, Arlett CF, Miki T, Weissman SM, Lovett M, Collins FS, Shiloh Y (1995) A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 268(5218):1749–1753 source

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    Premisecitation

    Singlet oxygen reacts with all four deoxynucleotide bases, preferring guanine, and produces 8-oxo-G as its main product.

    “Singlet oxygen reacts with all four deoxynucleotide bases with guanine as its preference, generating 8-oxo-7,8-dihydroguanine (8-oxo-G) as the major product [5].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [5] Agnez-Lima LF, Melo JT, Silva AE, Oliveira AH, Timoteo AR, Lima-Bessa KM, Martinez GR, Medeiros MH, Di Mascio P, Galhardo RS, Menck CF (2012) DNA damage by singlet oxygen and cellular protective mechanisms. Mutat Res 751(1):15–28. doi: 10.1016/j.mrrev.2011.12.005 source

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    Premisecitation

    Hydroxyl radicals attack DNA purines and pyrimidines by adding to double bonds and removing hydrogen from thymine methyl groups and deoxyribose C-H bonds, yielding products such as 5-hydroxymethyluracil, a C8-OH guanine adduct radical, and 8-hydroxyguanine.

    “Hydroxyl radicals can react with the purines and pyrimidines of DNA by the addition of double bonds and the abstraction of a H atom (H·) from the methyl group of thymine and from each of the C–H bonds of 2′-deoxyribose. This results in products, such as 5-hydroxymethyl-uracil, C8–OH–adduct radical of guanine, and 8-hydroxyguanine (8-OH-G) [22].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [22] Neeley WL, Essigmann JM (2006) Mechanisms of formation, genotoxicity, and mutation of guanine oxidation products. Chem Res Toxicol 19(4):491–505. doi: 10.1021/tx0600043 source

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    Premisereasoning

    The MRN complex acts as a double-strand break sensor, binds broken DNA ends, and recruits ATM there for activation.

    “Acting as a DSB sensor, the MRN complex binds to DSBs and recruits ATM to the broken DNA ends for activation.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    DNA damage response pathways are conserved surveillance mechanisms that coordinate DNA repair, cell cycle progression, transcription, apoptosis, and senescence.

    “To maintain genome stability, the DDR pathways are conserved surveillance mechanisms coordinating DNA repair, cell cycle progression, transcription, apoptosis, and senescence [19, 39–41].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [19] Ciccia A, Elledge SJ (2010) The DNA damage response: making it safe to play with knives. Mol Cell 40(2):179–204. doi: 10.1016/j.molcel.2010.09.019 source

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    • cites [39] Jackson SP, Bartek J (2009) The DNA-damage response in human biology and disease. Nature 461(7267):1071–1078. doi: 10.1038/nature08467 source

      Not checked in the free run.

    • cites [40] Marechal A, Zou L (2013) DNA damage sensing by the ATM and ATR kinases. Cold Spring Harb Perspect Biol 5(9):a012716. doi: 10.1101/cshperspect.a012716 source

      Not checked in the free run.

    • cites [41] Branzei D, Foiani M (2010) Maintaining genome stability at the replication fork. Nat Rev Mol Cell Biol 11(3):208–219. doi: 10.1038/nrm2852 source

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    Premisecitation

    Intrastrand crosslinks, interstrand crosslinks, double-strand breaks, and oxidatively generated clustered DNA lesions can form after ionizing radiation and ultraviolet radiation.

    “Intrastrand crosslinks, interstrand crosslinks, DSBs, and OCDLs can be formed after exposure to IR and UV radiations [21].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [21] Cadet J, Ravanat JL, TavernaPorro M, Menoni H, Angelov D (2012) Oxidatively generated complex DNA damage: tandem and clustered lesions. Cancer Lett 327(1–2):5–15. doi: 10.1016/j.canlet.2012.04.005 source

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    Premisecitation

    MDC1 is phosphorylated by ATM and relocalizes to damage sites containing MRN, γ-H2AX, and 53BP1, and it is indispensable for the ATM-dependent DNA damage checkpoint.

    “With a forkhead-associated (FHA) domain and two BRCT domains, MDC1 is phosphorylated by ATM and relocalizes to damage sites that contain the MRN complex, γ-H2AX, and 53BP1, thereby playing an indispensable role in ATM-dependent DNA damage checkpoint [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Goldberg M, Stucki M, Falck J, D’Amours D, Rahman D, Pappin D, Bartek J, Jackson SP (2003) MDC1 is required for the intra-S-phase DNA damage checkpoint. Nature 421(6926):952–956. doi: 10.1038/nature01445 source

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    Premisecitation

    Unrepaired double-strand breaks can cause chromosomal aberrations and loss of function of proteins needed for cell survival or viability.

    “If not repaired, DSBs can lead to chromosomal aberrations and the dysfunction of key proteins for cell survival or viability [45–47].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [45] Karagiannis TC, El-Osta A (2004) Double-strand breaks: signaling pathways and repair mechanisms. Cell Mol Life Sci 61(17):2137–2147. doi: 10.1007/s00018-004-4174-0 source

      Not checked in the free run.

    • cites [46] Khanna KK, Jackson SP (2001) DNA double-strand breaks: signaling, repair and the cancer connection. Nat Genet 27(3):247–254. doi: 10.1038/85798 source

      Not checked in the free run.

    • cites [47] van Gent DC, Hoeijmakers JH, Kanaar R (2001) Chromosomal stability and the DNA double-stranded break connection. Nat Rev Genet 2(3):196–206. doi: 10.1038/35056049 source

      Not checked in the free run.

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    Chemotherapeutic agents can generate oxidative DNA damage; artesunate can induce 1,N6-ethenoadenine, single-strand breaks, and replication-associated double-strand breaks.

    “Chem-otherapeutic agents can generate oxidative DNA damage. For example, artesunate can induce 1,N6-ethenoadenine, SSBs and replication-associated DSBs [23–25].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [23] Litwin I, Bocer T, Dziadkowiec D, Wysocki R (2013) Oxidative stress and replication-independent DNA breakage induced by arsenic in Saccharomyces cerevisiae. PLoS Genet 9(7):e1003640. doi: 10.1371/journal.pgen.1003640 source

      Not checked in the free run.

    • cites [24] Kessel M, Liu SX, Xu A, Santella R, Hei TK (2002) Arsenic induces oxidative DNA damage in mammalian cells. Mol Cell Biochem 234–235(1–2):301–308 source

      Not checked in the free run.

    • cites [25] Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B (2011) Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells. Mol Cancer Ther 10(12):2224–2233. doi: 10.1158/1535-7163.MCT-11-0534 source

      Not checked in the free run.

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    During DNA replication, an oxidatively damaged site can be bypassed by inserting a mismatched deoxynucleotide such as 8-oxo-G:A.

    “During DNA replication, an oxidatively damaged site may be bypassed by incorporating a mismatched deoxynucleotide (e.g., 8-oxo-G:A) [7].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [7] Berquist BR, Wilson DM 3rd (2012) Pathways for repairing and tolerating the spectrum of oxidative DNA lesions. Cancer Lett 327(1–2):61–72. doi: 10.1016/j.canlet.2012.02.001 source

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    Defects in DNA repair and DNA damage response pathways can lead to human diseases such as cancer and neurodegenerative diseases.

    “Defective DNA repair and DDR pathways may lead to several human diseases, such as cancer and neurodegenerative diseases [6, 33–38]”
    Quote in the paperNot a substantial claim0 of 7 sources checked
    • cites [6] Ames BN, Shigenaga MK, Hagen TM (1993) Oxidants, antioxidants, and the degenerative diseases of aging. Proc Natl Acad Sci USA 90(17):7915–7922 source

      Not checked in the free run.

    • cites [33] Wallace SS, Murphy DL, Sweasy JB (2012) Base excision repair and cancer. Cancer Lett 327(1–2):73–89. doi: 10.1016/j.canlet.2011.12.038 source

      Not checked in the free run.

    • cites [34] Raetz AG, Xie Y, Kundu S, Brinkmeyer MK, Chang C, David SS (2012) Cancer-associated variants and a common polymorphism of MUTYH exhibit reduced repair of oxidative DNA damage using a GFP-based assay in mammalian cells. Carcinogenesis 33(11):2301–2309. doi: 10.1093/carcin/bgs270 source

      Not checked in the free run.

    • cites [35] Xiao X, Melton DW, Gourley C (2013) Mismatch repair deficiency in ovarian cancer—molecular characteristics and clinical implications. Gynecol Oncol 132(2):506–512. doi: 10.1016/j.ygyno.2013.12.003 source

      Not checked in the free run.

    • cites [36] Helleday T, Petermann E, Lundin C, Hodgson B, Sharma RA (2008) DNA repair pathways as targets for cancer therapy. Nat Rev Cancer 8(3):193–204. doi: 10.1038/nrc2342 source

      Not checked in the free run.

    • cites [37] Bouwman P, Jonkers J (2012) The effects of deregulated DNA damage signalling on cancer chemotherapy response and resistance. Nat Rev Cancer 12(9):587–598. doi: 10.1038/nrc3342 source

      Not checked in the free run.

    • cites [38] Hegde ML, Mantha AK, Hazra TK, Bhakat KK, Mitra S, Szczesny B (2012) Oxidative genome damage and its repair: implications in aging and neurodegenerative diseases. Mech Ageing Dev 133(4):157–168. doi: 10.1016/j.mad.2012.01.005 source

      Not checked in the free run.

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    Premisecitation

    RNF4, a SUMO-targeted ubiquitin E3 ligase, is recruited to double-strand breaks by MDC1 and promotes DNA repair and the cellular response to double-strand breaks.

    “RNF4, a SUMO-targeted ubiquitin E3 ligase, is recruited to DSBs by MDC1 and promotes DNA repair and cellular response to DSBs [66, 67].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Yin Y, Seifert A, Chua JS, Maure JF, Golebiowski F, Hay RT (2012) SUMO-targeted ubiquitin E3 ligase RNF4 is required for the response of human cells to DNA damage. Genes Dev 26(11):1196–1208. doi: 10.1101/gad.189274.112 source

      Not checked in the free run.

    • cites [67] Galanty Y, Belotserkovskaya R, Coates J, Jackson SP (2012) RNF4, a SUMO-targeted ubiquitin E3 ligase, promotes DNA double-strand break repair. Genes Dev 26(11):1179–1195. doi: 10.1101/gad.188284.112 source

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    Premisecitation

    Chk1 phosphorylation increases its kinase activity, allowing it to phosphorylate substrates such as Cdc25, BLM, and FANCD2/FANCE and to promote cell cycle arrest and DNA repair.

    “The phosphorylation of Chk1 enhances Chk1’s kinase activity, which in turn phosphorylates downstream substrates (e.g., Cdc25, BLM, and FANCD2/FANCE) and facilitates cell cycle arrest and DNA damage repair [91–93].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [91] Sanchez Y (1997) Conservation of the Chk1 checkpoint pathway in mammals: linkage of DNA damage to Cdk regulation through Cdc25. Science 277(5331):1497–1501. doi: 10.1126/science.277.5331.1497 source

      Not checked in the free run.

    • cites [92] Boddy MN (1998) Replication checkpoint enforced by kinases Cds1 and Chk1. Science 280(5365):909–912. doi: 10.1126/science.280.5365.909 source

      Not checked in the free run.

    • cites [93] Zhang Y, Hunter T (2013) Roles of Chk1 in cell biology and cancer therapy. Int J Cancer 134(5):1013–1023. doi: 10.1002/ijc.28226 source

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    Aberrant ATR expression causes Seckel syndrome, an autosomal recessive disorder with growth retardation and microcephaly.

    “Aberrant expression of ATR results in Seckel syndrome, an autosomal recessive disorder associated with growth retardation and microcephaly [82].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [82] O’Driscoll M, Ruiz-Perez VL, Woods CG, Jeggo PA, Goodship JA (2003) A splicing mutation affecting expression of ataxia-telangiectasia and Rad3-related protein (ATR) results in Seckel syndrome. Nat Genet 33(4):497–501. doi: 10.1038/ng1129 source

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    Hydrogen peroxide induces p53 phosphorylation at serine 15 and cell cycle arrest in an ATM-dependent manner in human umbilical vein endothelial cells.

    “Hydrogen peroxide induces p53 phosphorylation at Serine 15 and cell cycle arrest in an ATM-dependent manner in human umbilical vein endothelial cells [70].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [70] Chen K, Albano A, Ho A, Keaney JF Jr (2003) Activation of p53 by oxidative stress involves platelet-derived growth factor-beta receptor-mediated ataxia telangiectasia mutated (ATM) kinase activation. J Biol Chem 278(41):39527–39533. doi: 10.1074/jbc.M304423200 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM can be directly activated by hydrogen peroxide-induced oxidation without DNA damage, as shown by ATM autophosphorylation at serine 1981, p53 phosphorylation at serine 15, and Chk2 phosphorylation at threonine 68, but not H2AX phosphorylation at serine 139.

    “Notably, ATM was directly activated by hydrogen peroxide-induced oxidation in the absence of DNA damage, evidenced by ATM auto-phosphorylation at Serine 1981, p53 phosphorylation at Serine 15, and Chk2 phosphorylation at Threonine 68, but not by H2AX phosphorylation at Serine139 [74–76].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [74] Guo Z, Kozlov S, Lavin MF, Person MD, Paull TT (2010) ATM activation by oxidative stress. Science 330(6003):517–521. doi: 10.1126/science.1192912 source

      Not checked in the free run.

    • cites [75] Ambrose M, Gatti RA (2013) Pathogenesis of ataxia-telangiectasia: the next generation of ATM functions. Blood 121(20):4036–4045. doi: 10.1182/blood-2012-09-456897 source

      Not checked in the free run.

    • cites [76] Bhatti S, Kozlov S, Farooqi AA, Naqi A, Lavin M, Khanna KK (2011) ATM protein kinase: the linchpin of cellular defenses to stress. Cell Mol Life Sci 68(18):2977–3006. doi: 10.1007/s00018-011-0683-9 source

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  • May combine two claims.

    Premisecitation

    The Tim-Tipin complex associates with ATR-Chk1 checkpoint proteins and plays an essential role in the DNA damage response.

    “The circadian protein Tim (Timeless) -Tipin (Timeless-interacting protein) complex associates with ATR-Chk1 checkpoint proteins and plays an essential role in DDR as well [130–133].”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [130] Unsal-Kacmaz K, Mullen TE, Kaufmann WK, Sancar A (2005) Coupling of human circadian and cell cycles by the timeless protein. Mol Cell Biol 25(8):3109–3116. doi: 10.1128/MCB.25.8.3109-3116.2005 source

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    • cites [131] Unsal-Kacmaz K, Chastain PD, Qu PP, Minoo P, Cordeiro-Stone M, Sancar A, Kaufmann WK (2007) The human Tim/Tipin complex coordinates an Intra-S checkpoint response to UV that slows replication fork displacement. Mol Cell Biol 27(8):3131–3142. doi: 10.1128/MCB.02190-06 source

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    • cites [132] Errico A, Costanzo V, Hunt T (2007) Tipin is required for stalled replication forks to resume DNA replication after removal of aphidicolin in Xenopus egg extracts. Proc Natl Acad Sci USA 104(38):14929–14934. doi: 10.1073/pnas.0706347104 source

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    • cites [133] Errico A, Costanzo V (2012) Mechanisms of replication fork protection: a safeguard for genome stability. Crit Rev Biochem Mol Biol 47(3):222–235. doi: 10.3109/10409238.2012.655374 source

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  • May combine two claims.

    Premisecitation

    ATMIN is an essential component of the ATM checkpoint pathway in oxidative stress; it mediates oxidative stress-induced ATM activity and protects the aging brain from DNA damage accumulation.

    “ATMIN, an ATM interactor protein, was identified as an essential component in the ATM checkpoint pathway in response to oxidative stress. ATMIN mediates oxidative stress-induced ATM activity, thereby protecting the aging brain from accumulating DNA damage [78].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [78] Kanu N, Penicud K, Hristova M, Wong B, Irvine E, Plattner F, Raivich G, Behrens A (2010) The ATM cofactor ATMIN protects against oxidative stress and accumulation of DNA damage in the aging brain. J Biol Chem 285(49):38534–38542. doi: 10.1074/jbc.M110.145896 source

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  • May combine two claims.

    Premisecitation

    Ochratoxin A induces oxidative DNA damage and triggers ATM-dependent G2 arrest in human gastric epithelium GES-1 cells.

    “Ochratoxin A, one of the most abundant mycotoxin food contaminants, induces oxidative DNA damage and triggers an ATM-dependent G2 arrest in human gastric epithelium GES-1 cells [72].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Cui J, Liu J, Wu S, Wang Y, Shen H, Xing L, Wang J, Yan X, Zhang X (2013) Oxidative DNA damage is involved in ochratoxin A-induced G2 arrest through ataxia telangiectasia-mutated (ATM) pathways in human gastric epithelium GES-1 cells in vitro. Arch Toxicol 87(10):1829–1840. doi: 10.1007/s00204-013-1043-3 source

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

    Premisecitation

    ATR is essential for early embryonic development.

    “ATR was originally cloned as a member of the phosphoinositide 3-kinase–related kinase (PIKK) family and is essential for early embryonic development [32, 80, 81].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [32] Cimprich KA, Cortez D (2008) ATR: an essential regulator of genome integrity. Nat Rev Mol Cell Biol 9(8):616–627. doi: 10.1038/nrm2450 source

      Not checked in the free run.

    • cites [80] Cimprich KA, Shin TB, Keith CT, Schreiber SL (1996) cDNA cloning and gene mapping of a candidate human cell cycle checkpoint protein. Proc Natl Acad Sci USA 93(7):2850–2855 source

      Not checked in the free run.

    • cites [81] Brown EJ, Baltimore D (2000) ATR disruption leads to chromosomal fragmentation and early embryonic lethality. Genes Dev 14(4):397–402 source

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  • May combine two claims.

    Premisecitation

    ATM−/− ataxia-telangiectasia fibroblasts are more susceptible to oxidative stress than normal cells, leading to the proposal that ATM is a major sensor of oxidative DNA damage or ROS.

    “As A-T fibroblast cells (ATM−/−) are more susceptible to oxidative stress than normal cells, ATM was proposed as a major sensor of oxidative DNA damage or ROS [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Rotman G, Shiloh Y (1997) Ataxia-telangiectasia: is ATM a sensor of oxidative damage and stress? BioEssays 19(10):911–917. doi: 10.1002/bies.950191011 source

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  • May combine two claims.

    Premisecitation

    The ATR-ATRIP complex and the 9-1-1 complex are recruited to RPA-coated single-stranded DNA independently and are bridged by TopBP1.

    “The ATR-ATRIP complex and 9-1-1 complexes are recruited to RPA-ssDNA independently and are bridged by the multiple-function protein TopBP1 (Topoisomerase IIβ binding protein 1) [106–110].”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [106] Kondo T, Wakayama T, Naiki T, Matsumoto K, Sugimoto K (2001) Recruitment of Mec1 and Ddc1 checkpoint proteins to double-strand breaks through distinct mechanisms. Science 294(5543):867–870. doi: 10.1126/science.1063827 source

      Not checked in the free run.

    • cites [107] Melo JA, Cohen J, Toczyski DP (2001) Two checkpoint complexes are independently recruited to sites of DNA damage in vivo. Genes Dev 15(21):2809–2821. doi: 10.1101/gad.903501 source

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    • cites [108] Kanoh Y, Tamai K, Shirahige K (2006) Different requirements for the association of ATR-ATRIP and 9-1-1 to the stalled replication forks. Gene 377:88–95. doi: 10.1016/j.gene.2006.03.019 source

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    • cites [109] Garcia V, Furuya K, Carr AM (2005) Identification and functional analysis of TopBP1 and its homologs. DNA Repair (Amst) 4(11):1227–1239. doi: 10.1016/j.dnarep.2005.04.001 source

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    • cites [110] Sokka M, Parkkinen S, Pospiech H, Syvaoja JE (2010) Function of TopBP1 in genome stability. Subcell Biochem 50:119–141. doi: 10.1007/978-90-481-3471-7_7 source

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  • May combine two claims.

    Premisecitation

    Hydrogen peroxide represses mTORC1 in a dose- and time-dependent way, and this repression by ROS requires cytoplasmic ATM, suggesting a subcellular compartment requirement for ATM signaling in oxidative stress.

    “Hydrogen peroxide represses mTORC1 in a dose and time-dependent manner, and the mTORC1 repression by ROS requires the presence of ATM in the cytoplasm, suggesting a sub-cellular compartment requirement for ATM signaling in oxidative stress [77].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [77] Alexander A, Cai SL, Kim J, Nanez A, Sahin M, MacLean KH, Inoki K, Guan KL, Shen J, Person MD, Kusewitt D, Mills GB, Kastan MB, Walker CL (2010) ATM signals to TSC2 in the cytoplasm to regulate mTORC1 in response to ROS. Proc Natl Acad Sci USA 107(9):4153–4158. doi: 10.1073/pnas.0913860107 source

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  • May combine two claims.

    Premisecitation

    Long single-stranded DNA can be generated by uncoupling MCM helicase and DNA polymerase during replication stress, by CtIP-mediated double-strand break end resection, by Exo1-mediated processing of nucleotide excision repair intermediates after UV, and by APE2-mediated single-strand break end resection in oxidative stress.

    “A long stretch of ssDNA can be generated through the functional uncoupling of minichromosome maintenance (MCM) helicase and DNA polymerase in DNA replication stress, the DSB end resection by DNA exonuclease such as CtIP in DSB response, the Exo1-mediated processing of NER intermediates after UV radiation, and the SSB end resection by AP endonuclease 2 (APE2) in oxidative stress [86, 97–99]”
    Quote in the paperSubstantial claim0 of 4 sources checked
    • cites [86] Willis J, Patel Y, Lentz BL, Yan S (2013) APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. Proc Natl Acad Sci USA 110(26):10592–10597. doi: 10.1073/pnas.1301445110 source

      Not checked in the free run.

    • cites [97] Byun TS, Pacek M, Yee MC, Walter JC, Cimprich KA (2005) Functional uncoupling of MCM helicase and DNA polymerase activities activates the ATR-dependent checkpoint. Genes Dev 19(9):1040–1052. doi: 10.1101/gad.1301205 source

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    • cites [98] You Z, Shi LZ, Zhu Q, Wu P, Zhang YW, Basilio A, Tonnu N, Verma IM, Berns MW, Hunter T (2009) CtIP links DNA double-strand break sensing to resection. Mol Cell 36(6):954–969. doi: 10.1016/j.molcel.2009.12.002 source

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    • cites [99] Giannattasio M, Follonier C, Tourriere H, Puddu F, Lazzaro F, Pasero P, Lopes M, Plevani P, Muzi-Falconi M (2010) Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation. Mol Cell 40(1):50–62. doi: 10.1016/j.molcel.2010.09.004 source

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  • May combine two claims.

    Premisecitation

    UV-induced replication stress triggers ATM phosphorylation at serine 1981, Chk2 phosphorylation at threonine 68, and H2AX phosphorylation at serine 139.

    “UV-induced replication stress triggers ATM phosphorylation at Serine 1981, Chk2 phosphorylation at Threonine 68, and H2AX phosphorylation at Serine 139.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In response to temozolomide, the ATR-Chk1 checkpoint is activated to arrest the cell cycle at G2/M, followed by ATM-Chk2 activation, suggesting ATR acts earlier than ATM.

    “Alternatively, in response to the DNA methylating agent temozolomide, the ATR-Chk1 checkpoint is activated to arrest cell cycle at G2/M transition. This is followed by ATM-Chk2 checkpoint activation, suggesting ATR functions earlier than ATM [143].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [143] Caporali S, Falcinelli S, Starace G, Russo MT, Bonmassar E, Jiricny J, D’Atri S (2004) DNA damage induced by temozolomide signals to both ATM and ATR: role of the mismatch repair system. Mol Pharmacol 66(3):478–491. doi: 10.1124/mol.66.3 source

      Not checked in the free run.

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

    Premisecitation

    An ATM-to-ATR switch during the biphasic double-strand break response was proposed in a study using mammalian cell lysates.

    “Additionally, an ATM-to-ATR switch during the biphasic DSB response was proposed in a report using mammalian cell lysates [141].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [141] Shiotani B, Zou L (2009) Single-stranded DNA orchestrates an ATM-to-ATR switch at DNA breaks. Mol Cell 33(5):547–558. doi: 10.1016/j.molcel.2009.01.024 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM is essential for recruiting ATR to ionizing radiation-damaged chromatin and for Chk1 phosphorylation at serine 345.

    “ATM is essential for the recruitment of ATR to IR-damaged chromatin and Chk1 phosphorylation at Serine 345 [139].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [139] Cuadrado M, Martinez-Pastor B, Murga M, Toledo LI, Gutierrez-Martinez P, Lopez E, Fernandez-Capetillo O (2006) ATM regulates ATR chromatin loading in response to DNA double-strand breaks. J Exp Med 203(2):297–303. doi: 10.1084/jem.20051923 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    4-Hydroxynonenal induces caffeine-sensitive ATR phosphorylation at serine 428 and Chk1 phosphorylation at serine 296.

    “HNE also induces caffeine-sensitive ATR phosphorylation at Serine 428 and Chk1 phosphorylation at Serine 296 [147].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [147] Chaudhary P, Sharma R, Sahu M, Vishwanatha JK, Awasthi S, Awasthi YC (2013) 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. J Biol Chem 288(28):20532–20546. doi: 10.1074/jbc.M113.467662 source

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  • May combine two claims.

    Interpretationcitation

    There is crosstalk and transition between the ATM-Chk2 and ATR-Chk1 pathways.

    “However, there is a suggestion of crosstalk and transition between these two pathways.”
    Quote in the paperSubstantial claim

  • Classified as probably not a substantial claim. May combine two claims.

    Premisecitation

    DDR kinases promote efficient DNA repair by directly regulating DNA repair machinery and changing the local chromatin and cellular environment.

    “It was proposed recently that DDR kinases promote efficient DNA repair by directly regulating the DNA repair machinery, changing the local chromatin environment and cellular environment [166].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [166] Sirbu BM, Cortez D (2013) DNA damage response: three levels of DNA repair regulation. Cold Spring Harb Perspect Biol 5(8):a012724. doi: 10.1101/cshperspect.a012724 source

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  • May combine two claims.

    Interpretationcitation

    Several studies support roles for ATM-Chk2 and ATR-Chk1 pathways in BER, NER, MMR, and HR during the cellular response to oxidative stress, but the exact molecular mechanisms remain unclear.

    “Several studies support the role of ATM-Chk2 and ATR-Chk1 pathways for BER, NER, MMR and HR pathways in cellular response to oxidative stress; however, molecular mechanisms of how exactly DDR pathways regulate DNA repair pathways in oxidative stress require more clarity.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Eliminating ATM kinase activity with KU55933 does not affect hydrogen peroxide-induced Chk1 phosphorylation, suggesting ATM may be nonessential for ATR-Chk1 checkpoint activation in oxidative stress.

    “However, eliminating ATM kinase activity by its specific inhibitor KU55933 does not affect hydrogen peroxide-induced Chk1 phosphorylation, suggesting ATM may be nonessential for ATR-Chk1 checkpoint activation in oxidative stress response [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Willis J, Patel Y, Lentz BL, Yan S (2013) APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. Proc Natl Acad Sci USA 110(26):10592–10597. doi: 10.1073/pnas.1301445110 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    ATM and ATR may be activated sequentially, with the order depending on the nature of the DNA damage or stress (double-strand breaks versus stalled replication forks or UV radiation), and there is direct crosstalk between the two DDR kinases.

    “These findings suggest that ATM and ATR may be activated sequentially, the order of which is dependent on the nature of DNA damage or stress (DSBs versus stalled replication forks or UV radiation), and that there is direct cross talk between the two key DDR kinases.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Hydrogen peroxide triggers both ATM phosphorylation at serine 1981 and Chk1 phosphorylation at serine 344 in Xenopus egg extracts.

    “Hydrogen peroxide triggers both ATM phosphorylation at Serine 1981 and Chk1 phosphorylation at Serine 344 in Xenopus egg extracts [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Willis J, Patel Y, Lentz BL, Yan S (2013) APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. Proc Natl Acad Sci USA 110(26):10592–10597. doi: 10.1073/pnas.1301445110 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Artesunate can cause oxidative DNA damage and trigger phosphorylation of ATM, Chk2, Chk1, and H2AX, and may eventually lead to apoptosis in human glioblastoma cells.

    “Artesunate can cause oxidative DNA damage and trigger the phosphorylation of ATM, Chk2, Chk1, and H2AX, and eventually may lead to apoptosis in human glioblastoma cells [25].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [25] Berdelle N, Nikolova T, Quiros S, Efferth T, Kaina B (2011) Artesunate induces oxidative DNA damage, sustained DNA double-strand breaks, and the ATM/ATR damage response in cancer cells. Mol Cancer Ther 10(12):2224–2233. doi: 10.1158/1535-7163.MCT-11-0534 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    TDP1 protects against oxidative DNA damage and has been implicated in single-strand break repair.

    “TDP1 protects against oxidative DNA damage and has been implicated in SSBR [169].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [169] Meagher M, Lightowlers RN (2014) The role of TDP1 and APTX in mitochondrial DNA repair. Biochimie 100:121–124. doi: 10.1016/j.biochi.2013.10.011 source

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  • May combine two claims.

    Premisecitation

    Lycopene inhibits H. pylori-induced gastric diseases associated with oxidative DNA damage such as 8-OH-G and double-strand breaks and prevents ROS-induced ATM- and ATR-mediated DNA damage response in gastric epithelial AGS cells.

    “In addition, the natural antioxidant Lycopene inhibits H. pylori-induced gastric diseases associated with oxidative DNA damage (e.g., 8–OH–G and DSBs) and prevents ROS-induced ATM- and ATR-mediated DDR in gastric epithelial AGS cells [138].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [138] Jang SH, Lim JW, Morio T, Kim H (2012) Lycopene inhibits Helicobacter pylori-induced ATM/ATR-dependent DNA damage response in gastric epithelial AGS cells. Free Radic Biol Med 52(3):607–615. doi: 10.1016/j.freeradbiomed.2011.11.010 source

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  • May combine two claims.

    Premisecitation

    Selenium compounds and their metabolites such as Na2SeO3, MSeA, or MSeC induce ROS including 8-oxo-G and cause MLH1-mediated G2/M arrest in HCT116 cells.

    “The selenium compound and its metabolites (e.g., Na2SeO3, MSeA, or MSeC) induce ROS, such as 8-oxo-G, and cause MLH1-mediated and G2/M arrest in HCT116 [172].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [172] Qi Y, Schoene NW, Lartey FM, Cheng WH (2010) Selenium compounds activate ATM-dependent DNA damage response via the mismatch repair protein hMLH1 in colorectal cancer cells. J Biol Chem 285(43):33010–33017. doi: 10.1074/jbc.M110.137406 source

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  • May combine two claims.

    Premisecitation

    4-Hydroxynonenal-induced double-strand breaks enhance comet tail formation and H2AX phosphorylation in hepatocellular carcinoma cells, suggesting ATM activation.

    “4-Hydroxynonenal (HNE)-induced DSBs enhance comet tail formation and H2AX phosphorylation in hepatocellular carcinoma cells, suggesting ATM activation [147–149].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [147] Chaudhary P, Sharma R, Sahu M, Vishwanatha JK, Awasthi S, Awasthi YC (2013) 4-Hydroxynonenal induces G2/M phase cell cycle arrest by activation of the ataxia telangiectasia mutated and Rad3-related protein (ATR)/checkpoint kinase 1 (Chk1) signaling pathway. J Biol Chem 288(28):20532–20546. doi: 10.1074/jbc.M113.467662 source

      Not checked in the free run.

    • cites [148] Ward IM, Chen J (2001) Histone H2AX is phosphorylated in an ATR-dependent manner in response to replicational stress. J Biol Chem 276(51):47759–47762. doi: 10.1074/jbc.C100569200 source

      Not checked in the free run.

    • cites [149] Burma S, Chen BP, Murphy M, Kurimasa A, Chen DJ (2001) ATM phosphorylates histone H2AX in response to DNA double-strand breaks. J Biol Chem 276(45):42462–42467. doi: 10.1074/jbc.C100466200 source

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  • May combine two claims.

    Premisecitation

    Hydrogen peroxide triggers ATR-Chk1 checkpoint signaling in human dermal fibroblasts HDF cells and in Xenopus egg extracts.

    “More recently, it has been demonstrated that hydrogen peroxide triggers ATR-Chk1 checkpoint signaling in human dermal fibroblasts HDF cells [137] and in Xenopus egg extracts [86].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [137] Yang Y, Durando M, Smith-Roe SL, Sproul C, Greenwalt AM, Kaufmann W, Oh S, Hendrickson EA, Vaziri C (2013) Cell cycle stage-specific roles of Rad18 in tolerance and repair of oxidative DNA damage. Nucleic Acids Res 41(4):2296–2312. doi: 10.1093/nar/gks1325 source

      Not checked in the free run.

    • cites [86] Willis J, Patel Y, Lentz BL, Yan S (2013) APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. Proc Natl Acad Sci USA 110(26):10592–10597. doi: 10.1073/pnas.1301445110 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM is essential for double-strand break-induced ATR activation in S and G2 phases but not in G1 phase.

    “Furthermore, ATM is essential for DSB-induced ATR activation in the S and G2 phases of cell cycle, but not in the G1 phase [140].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [140] Jazayeri A, Falck J, Lukas C, Bartek J, Smith GC, Lukas J, Jackson SP (2006) ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 8(1):37–45. doi: 10.1038/ncb1337 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In lung cancer cells with functional p53, cisplatin-induced XPA nuclear import requires the ATR checkpoint, whereas cells lacking p53 do not show this requirement.

    “Cisplatin-induced nuclear import of XPA is also dependent on an ATR checkpoint in p53-proficient, but not p53-deficient, lung cancer cells [191]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [191] Li Z, Musich PR, Zou Y (2011) Differential DNA damage responses in p53 proficient and deficient cells: cisplatin-induced nuclear import of XPA is independent of ATR checkpoint in p53-deficient lung cancer cells. Int J Biochem Mol Biol 2(2):138–145

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  • May combine two claims.

    Premisecitation

    ATM is essential for MLH1 phosphorylation at serine 406 and its stability after doxorubicin treatment, suggesting that ATM regulates mismatch repair proteins.

    “ATM is essential for MLH1 phosphorylation at Serine 406 and its stability following chemotherapy drug doxorubicin treatment, suggesting the regulation of MMR proteins by ATM [173].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [173] Romeo F, Falbo L, Di Sanzo M, Misaggi R, Faniello MC, Viglietto G, Cuda G, Costanzo F, Quaresima B (2011) BRCA1 is required for hMLH1 stabilization following doxorubicin-induced DNA damage. Int J Biochem Cell Biol 43(12):1754–1763. doi: 10.1016/j.biocel.2011.08.011 source

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  • May combine two claims.

    Premisecitation

    ATM plays an important role in recruiting the Ku complex to hydrogen peroxide-damaged chromatin, supporting a role for ATM in double-strand break repair by nonhomologous end joining.

    “Moreover, ATM plays an important role for the recruitment of Ku complex to hydrogen peroxide-damaged chromatin, further supporting the role of ATM in DSB repair by NHEJ [174, 175] (Fig. 6).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [174] Lee JH, Kim KH, Morio T, Kim H (2006) Ataxia-telangiectasia-mutated-dependent activation of Ku in human fibroblasts exposed to hydrogen peroxide. Ann NY Acad Sci 1091:76–82. doi: 10.1196/annals.1378.056 source

      Not checked in the free run.

    • cites [175] Kuhne C, Tjornhammar ML, Pongor S, Banks L, Simoncsits A (2003) Repair of a minimal DNA double-strand break by NHEJ requires DNA-PKcs and is controlled by the ATM/ATR checkpoint. Nucleic Acids Res 31(24):7227–7237 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Upon UV exposure, ATR phosphorylates XPA at serine 196 and controls XPA entry into the nucleus.

    “In response to UV damage, ATR phosphorylates XPA at Serine 196 and regulates the nuclear import of XPA”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [187] Wu X, Shell SM, Yang Z, Zou Y (2006) Phosphorylation of nucleotide excision repair factor xeroderma pigmentosum group A by ataxia telangiectasia mutated and Rad3-related-dependent checkpoint pathway promotes cell survival in response to UV irradiation. Cancer Res 66(6):2997–3005. doi: 10.1158/0008-5472.CAN-05-3403 source

      Not checked in the free run.

    • cites [188] Wu X, Shell SM, Liu Y, Zou Y (2007) ATR-dependent checkpoint modulates XPA nuclear import in response to UV irradiation. Oncogene 26(5):757–764. doi: 10.1038/sj.onc.1209828 source

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  • May combine two claims.

    Premisecitation

    DDB2 and XPC bring ATM and ATR to UV-damaged sites and enhance ATM-Chk2 and ATR-Chk1 checkpoint signaling.

    “DDB2 and XPC recruit ATM and ATR to UV-damaged sites and promote ATM-Chk2 and ATR-Chk1 checkpoint signaling.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [202] Marti TM, Hefner E, Feeney L, Natale V, Cleaver JE (2006) H2AX phosphorylation within the G1 phase after UV irradiation depends on nucleotide excision repair and not DNA double-strand breaks. Proc Natl Acad Sci USA 103(26):9891–9896. doi: 10.1073/pnas.0603779103 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In XRCC1-deficient cells, MMS produces unresolved BER intermediates and turns on ATM- and ATR-dependent DDR pathways, including S-phase delay and phosphorylation of SMC1 at serine 966 and Chk1 at serine 345.

    “MMS induces unresolved BER intermediates in XRCC1-deficient cells and activates ATM and ATR-dependent DDR pathways, including S-phase delay and SMC1 (structural maintenance of chromosomes protein 1) phosphorylation at Serine 966 and Chk1 phosphorylation at Serine 345 [199]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [199] Brem R, Fernet M, Chapot B, Hall J (2008) The methyl methanesulfonate induced S-phase delay in XRCC1-deficient cells requires ATM and ATR. DNA Repair (Amst) 7(6):849–857. doi: 10.1016/j.dnarep.2008.02.002 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA repair proteins, including DNA nucleases, can convert DNA damage into structures that recruit DDR proteins or can directly recruit DDR proteins to damaged sites through protein-protein interactions.

    “DNA repair proteins (such as DNA nucleases) may process DNA damage into structures for DDR protein recruitment or recruit DDR proteins to damaged sites via direct protein–protein interactions.”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [99] Giannattasio M, Follonier C, Tourriere H, Puddu F, Lazzaro F, Pasero P, Lopes M, Plevani P, Muzi-Falconi M (2010) Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation. Mol Cell 40(1):50–62. doi: 10.1016/j.molcel.2010.09.004 source

      Not checked in the free run.

    • cites [196] Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, Baskaran R (2003) The mismatch repair system is required for S-phase checkpoint activation. Nat Genet 33(1):80–84. doi: 10.1038/ng1052 source

      Not checked in the free run.

    • cites [197] Yoshioka K, Yoshioka Y, Hsieh P (2006) ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Mol Cell 22(4):501–510. doi: 10.1016/j.molcel.2006.04.023 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM is required for selenium-induced MLH1-PMS2 association, which is essential for repair efficiency.

    “Notably, ATM is required for the selenium-induced MLH1-PMS2 association, which is essential for the repair efficiency [172] (Fig. 5).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [172] Qi Y, Schoene NW, Lartey FM, Cheng WH (2010) Selenium compounds activate ATM-dependent DNA damage response via the mismatch repair protein hMLH1 in colorectal cancer cells. J Biol Chem 285(43):33010–33017. doi: 10.1074/jbc.M110.137406 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recruitment of the 9-1-1 complex to H2O2-damaged chromatin requires APE2-mediated generation of RPA-coated single-stranded DNA, suggesting that the 9-1-1 complex may promote BER through a positive feedback mechanism.

    “Importantly, the recruitment of the 9-1-1 complex to H2O2-damaged chromatin requires APE2-mediated generation of RPA-ssDNA, suggesting the 9-1-1 complex may promote the BER pathway via a positive feedback mechanism [86].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [86] Willis J, Patel Y, Lentz BL, Yan S (2013) APE2 is required for ATR-Chk1 checkpoint activation in response to oxidative stress. Proc Natl Acad Sci USA 110(26):10592–10597. doi: 10.1073/pnas.1301445110 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationcitation

    Global genome NER, but not transcription-coupled NER, is necessary for ATR-Chk1 checkpoint signaling.

    “suggesting that GG-NER but not TC-NER (transcription-coupled NER) is required for ATR-Chk1 checkpoint signaling [200]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [200] Marini F, Nardo T, Giannattasio M, Minuzzo M, Stefanini M, Plevani P, Muzi Falconi M (2006) DNA nucleotide excision repair-dependent signaling to checkpoint activation. Proc Natl Acad Sci USA 103(46):17325–17330. doi: 10.1073/pnas.0605446103 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    ATM and ATR appear unnecessary for recruiting DDB2 and XPC to UV-damaged sites and for NER repair of CPDs and 6-4PPs.

    “ATM and ATR seem to be not essential for the recruitment of DDB2 and XPC to UV-damage sites and the NER repair of CPD and 6–4PP [203]”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [203] Ray A, Milum K, Battu A, Wani G, 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 (Amst) 12(4):273–283. doi: 10.1016/j.dnarep.2013.01.003 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Interactions between MSH2 and Chk2 and between MLH1 and ATM promote recruitment of DDR proteins to IR-damaged sites and help ATM phosphorylate Chk2.

    “The interactions between MMR and DDR proteins (i.e., MSH2-Chk2 and MLH1-ATM) promote the recruitment of DDR proteins to IR-damaged sites and facilitate Chk2 phosphorylation by ATM [196]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, Baskaran R (2003) The mismatch repair system is required for S-phase checkpoint activation. Nat Genet 33(1):80–84. doi: 10.1038/ng1052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The MRN complex is needed to activate ATM-dependent DDR after double-strand breaks and ATR-dependent DDR after stalled replication forks.

    “The MRN complex is required for the activation of ATM and ATR-dependent DDR pathways in response to DSBs and stalled DNA replication forks, respectively [57, 125, 218].”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites [57] Lee JH, Paull TT (2004) Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 304(5667):93–96. doi: 10.1126/science.1091496 source

      Not checked in the free run.

    • cites [125] Duursma AM, Driscoll R, Elias JE, Cimprich KA (2013) A role for the MRN complex in ATR activation via TOPBP1 recruitment. Mol Cell 50(1):116–122. doi: 10.1016/j.molcel.2013.03.006 source

      Not checked in the free run.

    • cites [218] Williams RS, Williams JS, Tainer JA (2007) Mre11-Rad50-Nbs1 is a keystone complex connecting DNA repair machinery, double-strand break signaling, and the chromatin template. Biochem Cell Biol 85(4):509–520. doi: 10.1139/O07-069 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Exo1 localizes with XPA at damage sites after local UV irradiation in non-replicating cells and converts NER intermediates into single-stranded DNA to promote DDR signaling.

    “Exo1 localizes with XPA to damage sites after local UV irradiation in non-replicating cells and converts NER intermediates into ssDNA to promote DDR signaling [99, 205]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [99] Giannattasio M, Follonier C, Tourriere H, Puddu F, Lazzaro F, Pasero P, Lopes M, Plevani P, Muzi-Falconi M (2010) Exo1 competes with repair synthesis, converts NER intermediates to long ssDNA gaps, and promotes checkpoint activation. Mol Cell 40(1):50–62. doi: 10.1016/j.molcel.2010.09.004 source

      Not checked in the free run.

    • cites [205] Sertic S, Pizzi S, Cloney R, Lehmann AR, Marini F, Plevani P, Muzi-Falconi M (2011) Human exonuclease 1 connects nucleotide excision repair (NER) processing with checkpoint activation in response to UV irradiation. Proc Natl Acad Sci USA 108(33):13647–13652. doi: 10.1073/pnas.1108547108 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MutSα recognizes O6-methylguanine paired with thymine but not O6-methylguanine paired with cytosine.

    “MutSα specifically recognizes O6-meG:T mismatch, but not O6-meG:C”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [197] Yoshioka K, Yoshioka Y, Hsieh P (2006) ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Mol Cell 22(4):501–510. doi: 10.1016/j.molcel.2006.04.023 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    XPC and XPG are required for ATM recruitment to damage sites after cisplatin treatment, which prevents cisplatin-induced apoptosis.

    “XPC and XPG are essential for the recruitment of ATM to damage sites after cisplatin treatment, preventing cisplatin-induced apoptosis [204]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [204] Colton SL, Xu XS, Wang YA, Wang G (2006) The involvement of ataxia-telangiectasia mutated protein activation in nucleotide excision repair-facilitated cell survival with cisplatin treatment. J Biol Chem 281(37):27117–27125. doi: 10.1074/jbc.M602826200 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    SN1-type DNA alkylating agents produce DNA adducts such as O6-methylguanine and activate the ATR-Chk1 pathway.

    “SN1-type DNA alkylating agents induce DNA adducts, such as O6-meG (O6-methylguanine), and activate the ATR-Chk1 pathway.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [197] Yoshioka K, Yoshioka Y, Hsieh P (2006) ATR kinase activation mediated by MutSalpha and MutLalpha in response to cytotoxic O6-methylguanine adducts. Mol Cell 22(4):501–510. doi: 10.1016/j.molcel.2006.04.023 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FdU may be removed by the uracil glycosylase Smug1, protecting cells from death.

    “FdU may be excised by the uracil glycosylase Smug1 to protect cells from death [210, 211]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [210] Longley DB, Harkin DP, Johnston PG (2003) 5-fluorouracil: mechanisms of action and clinical strategies. Nat Rev Cancer 3(5):330–338. doi: 10.1038/nrc1074 source

      Not checked in the free run.

    • cites [211] An Q, Robins P, Lindahl T, Barnes DE (2007) 5-Fluorouracil incorporated into DNA is excised by the Smug1 DNA glycosylase to reduce drug cytotoxicity. Cancer Res 67(3):940–945. doi: 10.1158/0008-5472.CAN-06-2960 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MutSα associates with ATR, TopBP1, Claspin, and Chk1 but not with Rad17, Rad9, or RPA, while MutLα interacts only with TopBP1 and Claspin.

    “MutSα associates with ATR, TopBP1, Claspin, and Chk1 (but not Rad17, Rad9, or RPA), whereas MutLα interacts only with TopBP1 and Claspin [214]”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [214] Liu Y, Fang Y, Shao H, Lindsey-Boltz L, Sancar A, Modrich P (2010) Interactions of human mismatch repair proteins MutSalpha and MutLalpha with proteins of the ATR-Chk1 pathway. J Biol Chem 285(8):5974–5982. doi: 10.1074/jbc.M109.076109 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MSH2 binds Chk2, and MLH1 associates with ATM.

    “MSH2 binds to Chk2 and that MLH1 associates with ATM”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [196] Brown KD, Rathi A, Kamath R, Beardsley DI, Zhan Q, Mannino JL, Baskaran R (2003) The mismatch repair system is required for S-phase checkpoint activation. Nat Genet 33(1):80–84. doi: 10.1038/ng1052 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    CtIP is required for double-strand break end resection, recruitment of RPA and ATR to double-strand breaks, and subsequent ATR activation.

    “CtIP is required for DSB end resection, the recruitment of RPA and ATR to DSBs, and subsequent ATR activation [98, 220]”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [98] You Z, Shi LZ, Zhu Q, Wu P, Zhang YW, Basilio A, Tonnu N, Verma IM, Berns MW, Hunter T (2009) CtIP links DNA double-strand break sensing to resection. Mol Cell 36(6):954–969. doi: 10.1016/j.molcel.2009.12.002 source

      Not checked in the free run.

    • cites [220] Sartori AA, Lukas C, Coates J, Mistrik M, Fu S, Bartek J, Baer R, Lukas J, Jackson SP (2007) Human CtIP promotes DNA end resection. Nature 450(7169):509–514. doi: 10.1038/nature06337 source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Components of DNA repair and DDR pathways have become therapeutic targets and are being tested in laboratory and clinical studies.

    “factors involved in DNA repair and DDR pathways have become therapeutic targets and are currently being tested in both laboratory and clinical studies [151, 222]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [151] Curtin NJ (2012) DNA repair dysregulation from cancer driver to therapeutic target. Nat Rev Cancer 12(12):801–817. doi: 10.1038/nrc3399 source

      Not checked in the free run.

    • cites [222] Kastan MS, Bartek J (2004) Cell-cycle checkpoints and cancer. Nature 432:316–323 source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    After double-strand breaks, ATM may be recruited to break ends by the MRN complex and other proteins for activation, while ATR is activated after end resection by enzymes such as CtIP and Exo1.

    “Thus, in response to DSBs, ATM may be recruited to the DSB end by the MRN complex and other proteins for activation, whereas ATR is activated after DSB end resection by enzymes such as CtIP and Exo1”
    Quote in the paperSubstantial claim
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Authors
Yan, S., Sorrell, M., & Berman, Z.
Affiliations
University of North Carolina at Charlotte (US)
Corresponding author
Yan, Shan
ORCID
Venue
Cellular and Molecular Life Sciences
Publisher
Springer Science and Business Media LLC
Published
2014-06-20
Volume
71
Issue
20
Pages
3951-3967
ISSN
  • 1420-682X (ISSN-L)
  • 1420-9071
DOI
10.1007/s00018-014-1666-4
PMC
PMC4176976
OpenAlex
W2033918102
Semantic Scholar
c1f29eae29590d9aed98dbf27ad4dedb7b0e0a1b
Cited by
247
References
225
Citations by year
2026: 23 · 2025: 11 · 2024: 24 · 2023: 11 · 2022: 32 · 2021: 26 · 2020: 25 · 2019: 22 · 2018: 23 · 2017: 18 · 2016: 16 · 2015: 14 · 2014: 2
FWCI
1.57
Type
journal article
Language
en
Open access
Licence
www.springer.com/tdm (tdm)
Locations
  • Cellular and Molecular Life Sciences (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Institute of General Medical Sciences (R15GM101571)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Redox biology and oxidative stress
  • Health Sciences › Medicine › Radiology, Nuclear Medicine and Imaging › Effects of Radiation Exposure
Keywords
DNA damage response, DNA repair pathways, oxidative DNA damage, oxidative stress, genome stability, cell cycle checkpoints, apoptosis, cellular senescence, cancer, neurodegenerative diseases
MeSH terms
Checkpoint Kinase 1, DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Protein Kinases, Signal Transduction, Oxidative Stress, Ataxia Telangiectasia Mutated Proteins, Checkpoint Kinase 2

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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 2026-10-07.

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