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Cited by 2,039DNA Repair MechanismsCarcinogens and Genotoxicity AssessmentDNA and Nucleic Acid Chemistry

Mechanisms of DNA damage, repair, and mutagenesis

Open access
Chatterjee, Nimrat, Walker, Graham C.·2017·Environmental and Molecular Mutagenesis
DOI 10.1002/em.22087PMC PMC5474181
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Abstract

Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease‐states. However, robust DNA repair and damage‐bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival. Deviations in this fine‐tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability. Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important. In this introductory review, we will delineate mechanisms of DNA damage and the counteracting repair/tolerance pathways to provide insights into the molecular basis of genotoxicity in cells that lays the foundation for subsequent articles in this issue. Environ. Mol. Mutagen. 58:235–263, 2017. © 2017 Wiley Periodicals, Inc.

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Crossref · 10.1002/em.22087

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  • Premisecitation

    Such reactions fuel development of hereditary diseases and sporadic cancers.

    “Such inherently predisposed reactions of DNA with molecules from its immediate surroundings fuel the development of hereditary diseases and sporadic cancers [Visconti and Grieco, 2009; Reuter et al., 2010; Perrone et al., 2016].”
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    MMR contributes more than 100-fold to replication fidelity by correcting rare errors that escape proofreading.

    “In addition, the mismatch repair (MMR) pathway contributes to replication fidelity by more than 100-fold by correcting the rare errors that have escaped proofreading by replicative polymerases [Kunkel, 2004; Kunkel, 2009; Kunkel, 2011].”
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  • Premisecitation

    Topoisomerases remove superhelical tension on DNA during replication and transcription.

    “Another source of endogenous DNA damage results from the action of topoisomerase enzymes (for example: TOP I, TOP II, TOP III; 7 TOP genes are found in the human genome), which primarily remove superhelical tension on DNA during replication and transcription [Wang, 2002; Pommier et al., 2006].”
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    • cites Pommier et al., 2006

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  • Premisecitation

    Strand slippage at repetitive sequences causes insertions/deletions that can change reading frame.

    “Additional replication errors accumulate from strand slippage events at repetitive sequences causing insertions and deletions of nucleotides that can potentially change the reading frame [Viguera et al., 2001; Chatterjee N., 2013].”
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  • Premisecitation

    The majority of endogenous DNA damage arises from DNA engaging in hydrolytic and oxidative reactions with water and ROS naturally present in cells.

    “The majority of the endogenous DNA damage arises from the chemically active DNA engaging in hydrolytic and oxidative reactions with water and reactive oxygen species (ROS), respectively, that are naturally present within cells.”
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    Premisenone given

    Robust DNA repair and damage-bypass mechanisms protect DNA by removing or tolerating damage, ensuring survival.

    “However, robust DNA repair and damage-bypass mechanisms faithfully protect the DNA by either removing or tolerating the damage to ensure an overall survival.”
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    Premisecitation

    Replicative polymerases sometimes incorporate uracil or have compromised fidelity due to altered dNTP/rNTP concentrations.

    “Other times, the replicative polymerases incorrectly incorporate uracil in the DNA or end up with a compromised fidelity because of the alterations of the relative and absolute concentrations of dNTPs and rNTPs within the cell’s environment [Andersen et al., 2005; Vertessy and Toth, 2009; Kumar et al., 2011; Clausen et al., 2013; Buckland et al., 2014; Potenski and Klein, 2014].”
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    • cites Vertessy and Toth, 2009

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    • cites Kumar et al., 2011

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    Premisenone given

    Disruption or deregulation of DNA repair pathways results in genome instability, as seen in diverse cancers.

    “Deviations in this fine-tuning are known to destabilize cellular metabolic homeostasis, as exemplified in diverse cancers where disruption or deregulation of DNA repair pathways results in genome instability.”
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    Premisecitation

    TOP1 transiently nicks supercoiled DNA, facilitates rotation, then religates breaks.

    “TOP1, for example, transiently nicks the supercoiled DNA and facilitates rotation of the broken strand around the TOP1-bound DNA strand to relax the DNA. Thereafter, TOP1 religates the breaks by aligning the 5′-OH group of the DNA with the tyrosine-DNA phosphodiester bond to resolve the complex [Stewart et al., 1998; Carey et al., 2003].”
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    Premisecitation

    In many cancers, DNA repair, DNA damage tolerance, and DDR pathways are disrupted or deregulated, increasing mutagenesis and genomic instability and promoting cancer progression.

    “Not surprisingly, in many cancers, DNA repair, DNA damage tolerance and DDR pathways are disrupted or deregulated, which increases mutagenesis and genomic instability, thereby promoting cancer progression [Bouwman and Jonkers, 2012; Ghosal and Chen, 2013; Wolters and Schumacher, 2013].”
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    • cites Ghosal and Chen, 2013

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    Premisereasoning

    Incorrectly paired or incorporated nucleotides that escape proofreading and MMR become mutations in the next replication and are a major source of spontaneous mutagenesis.

    “These incorrectly paired/incorporated nucleotides that escape proofreading and MMR become mutations in the next round of replication and are a major source of spontaneous mutagenesis.”
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    Premisecitation

    Deaminated cytosine is rapidly removed by uracil-DNA glycosylase; the G:T pair from 5mC deamination is a substrate for TDG and slow MMR.

    “While deaminated cytosine is rapidly removed from DNA by uracil-DNA glycosylase, the G:T base pair resulting from deamination of 5-methylcytosine is instead a substrate for the thymine DNA glycosylase (TDG) and the relatively slow MMR process [Lindahl, 1979; Wiebauer and Jiricny, 1990; Waters and Swann, 1998].”
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    • cites Lindahl, 1979

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    • cites Wiebauer and Jiricny, 1990

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    • cites Waters and Swann, 1998

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    Premisecitation

    At low levels, ROS perform important cellular functions such as redox signaling and immune defense against pathogens.

    “At low levels, ROS species perform important cellular functions such as serving as cellular messengers in redox signaling reactions and effecting important defense responses to invading pathogens by the immune system [Errol C. Friedberg, 2005; Segal, 2005; Malle et al., 2007].”
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    • cites Segal, 2005

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    • cites Malle et al., 2007

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    Premisecitation

    Hydroxyl radicals react with DNA bases by adding to double bonds, abstracting hydrogen atoms from methyl groups, and attacking the sugar residue.

    “These electrophilic •OH radicals react with DNA bases by 1) adding to their double bonds, 2) abstracting hydrogen atoms from their methyl groups, and 3) attacking the sugar residue in their immediate vicinity [Breen and Murphy, 1995; Winterbourn, 2008].”
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    In a human cell, about 10,000 abasic sites are created per day; extreme pH and high temperatures increase their generation.

    “In a human cell, about 10,000 abasic sites are created per day; both extreme pH conditions and high temperatures positively impact their generation [Lindahl, 1993; Tropp, 2011].”
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    Premisecitation

    Hydroxyl radical produced by the Fenton reaction of H2O2 with Fe2+ is by far the most reactive and can damage DNA, proteins, and lipids.

    “Amongst these ROS species, the •OH radical, produced as a byproduct of a Fenton’s reaction of H2O2 with Fe2+, is by far the most reactive, and is capable of damaging DNA, proteins and lipids [Imlay et al., 1988; Dizdaroglu et al., 1991].”
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    Base deamination occurs more frequently in single-stranded than double-stranded DNA and is exacerbated by transient single strandedness during replication, transcription, and recombination.

    “Interestingly, these base deamination events occur at a much higher frequency in single-stranded versus double-stranded DNA and are often exacerbated by transient single strandedness during active replication, transcription and recombination [Lindahl, 1993; Yonekura et al., 2009].”
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    Premisecitation

    Most AP sites are removed by AP endonucleases that cleave at the 5' end and allow BER; alternatively, AP sites can be bypassed by TLS polymerases.

    “Most AP sites are effectively removed by AP endonucleases that cleave at their 5′ end and allow the BER pathway to repair them. Alternatively, AP sites can be bypassed by TLS polymerases [Chan et al., 2013].”
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    Premisecitation

    Deleterious consequences of ROS are regulated by restricting respiration in mitochondria, protecting DNA by histones, and quenching surplus ROS by SOD, catalase, and peroxiredoxin.

    “Ordinarily, the deleterious consequences of ROS are regulated in cells by 1) restricting respiration in the mitochondrial compartment, thereby protecting other cellular components, 2) protecting DNA by complexing it with histones, and 3) quenching of surplus ROS species by the anti-oxidant enzymes superoxide dismutase, catalase, and peroxiredoxin [Riley, 1994; Mates et al., 1999; Mates and Sanchez”
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    • cites Mates and Sanchez-Jimenez, 1999

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    Premisecitation

    Cytosine and 5mC are most frequently deaminated, but 5mC is deaminated three to four times more frequently than cytosine.

    “Cytosine and 5-methyl cytosine are the most frequently deaminated, but 5-methyl cytosine is deaminated three to four times more frequently than cytosine [Lindahl, 1979].”
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    Premisecitation

    8-oxo-G is formed from hydroxylation of C-8 of guanine; it pairs incorrectly with adenine instead of cytosine, adding to mutational load, and is further oxidized to secondary lesions.

    “Another biologically significant and major oxidative base lesion formed from hydroxylation of the C-8 residue of guanine is the saturated imidazole ring 7,8 dihydro-8-oxoguanine (8-oxo-G) (Figure 1C). 8-oxo-guanine pairs incorrectly with adenine instead of cytosine, thereby adding to the overall mutational load, and is further oxidized to other deleterious secondary DNA lesions because of its low”
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    • cites Kasai and Nishimura, 1984

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    Premisenone given

    Base deamination is a major source of spontaneous mutagenesis in human cells; C, A, G, and 5mC lose their exocyclic amine to become U, hypoxanthine, xanthine, and T.

    “Base deamination is a major source of spontaneous mutagenesis in human cells, where cytosine (C), adenine (A), guanine (G), and 5-methyl cytosine (5mC) in DNA lose their exocyclic amine to become uracil (U), hypoxanthine, xanthine and thymine (T), respectively (Figure 1B).”
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    Premisecitation

    Cytosine deamination is a normal route for somatic hypermutagenesis during antibody development via AID and APOBEC1, which mediate host defense against retroviruses.

    “Paradoxically, cytosine deamination is also a normal route for somatic hypermutagenesis during antibody development due to the action of the deaminase enzymes AID (activation-induced deaminase) and APOBEC1 (Apolipoprotein B mRNA editing enzyme catalytic polypeptide 1), which mediate host defense against reteroviruses [Goff, 2003; Blanc and Davidson, 2010; Chandra et al., 2015].”
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    Premisecitation

    The most conspicuous ROS are superoxide radicals, hydrogen peroxide, and hydroxyl radical.

    “The most conspicuous of the ROS species are the superoxide radicals (•O2−), hydrogen peroxide (H2O2), and the hydroxyl radical (•OH) [Tropp, 2011].”
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    Premisecitation

    ROS are byproducts of the electron transport chain during cellular respiration and are derived from catabolic oxidases, anabolic processes, and peroxisomal metabolism.

    “Reactive oxygen species (ROS) are the typical byproducts of the electron transport chain (ETC) during cellular respiration in aerobic organisms, and are additionally derived from catabolic oxidases, anabolic processes and peroxisomal metabolism [Henle and Linn, 1997].”
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    Premisecitation

    About 1 adduct per 10^6-10^7 parent DNA bases results from lipid peroxidation; the number is expected to be higher for metal storage diseases Wilson's disease and hemochromatosis.

    “About 1 adduct per 106 – 107 parent DNA bases results from lipid peroxidation events and the number of mutagenic adducts are expected to be even higher for metal storage diseases such as Wilson’s disease and hemochromatosis [Carmichael et al., 1995; Luczaj and Skrzydlewska, 2003; Broedbaek et al., 2009].”
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    Premisecitation

    The DNA damage response is a collection of mechanisms that sense DNA damage, signal its presence, and promote subsequent repair.

    “The DDR is a collection of mechanisms that sense DNA damage, signal its presence and promote subsequent repair [Harper and Elledge, 2007].”
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    Interpretationreasoning

    DNA repair pathways effectively remove most DNA lesions, which could otherwise cause mutations or block replication and transcription, leading to senescence and cell death.

    “However, DNA repair pathways (Figure 4) effectively remove most DNA lesions, which could otherwise result in the formation of mutations or block metabolic processes such as replication and transcription thereby causing senescence and cell death as we discuss below.”
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    Premisecitation

    BER repairs oxidized bases; DNA backbone breaks are repaired by SSBR or DSBR pathways.

    “While the BER pathway repairs the oxidized bases, the breaks in the DNA backbone are repaired by the single strand break repair (SSBR) pathways or the double strand break repair (DSBR) pathways [Henner et al., 1983a; Demple and Harrison, 1994].”
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    There are nine human homologs of E. coli AlkB, designated ALKBH1-8 and FTO.

    “There are 9 human homologs of E. coli AlkB, which are designated as ALKBH1-8 (Alkylation Repair Homologs) and FTO (Fat Mass and Obesity associated) in human cells [Kurowski et al., 2003; Gerken et al., 2007; Sanchez-Pulido and Andrade-Navarro, 2007; Yi and He, 2013].”
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    • cites Sanchez-Pulido and Andrade-Navarro, 2007

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    At least 11 different DNA glycosylases can recognize and excise a damaged base from undistorted helices and from bases flipped out from the major groove.

    “At least 11 different DNA glycosylases can recognize and excise a damaged base from undistorted helices, as well as ones flipped out from the major groove [Huffman et al., 2005; Krokan and Bjoras, 2013].”
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    • cites Krokan and Bjoras, 2013

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    Premisecitation

    N3-methyladenine is partly cytotoxic due to inhibition of DNA synthesis; N7-methylguanine is essentially harmless unless it cleaves to an AP site or opens the imidazole ring to form formamidopyrimidine.

    “In contrast, N3-methyladenine is only partly cytotoxic due to inhibition of DNA synthesis, while the N7-methylguanine residue is essentially harmless unless it undergoes a spontaneous cleavage to generate an AP site or opens the imidazole ring to form formamidopyrimidine [Loveless, 1969; Loechler et al., 1984; Larson et al., 1985; Preston et al., 1986; Preston et al., 1987; O’Connor et al., 1988;”
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    • cites Loechler et al., 1984

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    • cites Larson et al., 1985

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    Premisenone given

    O6-methylguanine and related O4-methylthymine and O4-ethylthymine are highly mutagenic, producing G:C→A:T and T:A→C:G transitions.

    “O6-methylguanine and the related residues O4-methylthymine and O4-ethylthymine are highly mutagenic, producing G:C→A:T and T:A→C:G transition mutations, respectively.”
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    Premisecitation

    In short-patch BER, APE1 cleaves 5′ to the abasic site, generating a 3′-hydroxyl and a 5′-dRP; POL β tailors the gap and fills one nucleotide; LIG1 or LIG3-XRCC1 ligates.

    “In short patch repair, the abasic site is the substrate for the AP endonuclease (APE1 in human cells), which cleaves the phosphodiester bond 5′ to the abasic site and generates a hydroxyl residue at the 3′-end while leaving a deoxyribose phosphate (dRP) at the 5′-end. This repair gap is tailored by the 5′-dRP lyase activity of POL β (gap tailoring), followed by filling the single nucleotide gap by”
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    • cites Almeida and Sobol, 2007

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    Premisecitation

    For UV-induced CPDs, the UV-DDB complex (DDB1 and DDB2) binds UV lesions and stimulates XPC binding.

    “For repair of UV-induced CPDs, the ultraviolet-damaged DNA damage−binding protein (UV–DDB) complex, consisting of DDB1 (XPE−binding factor) and the GG−NER−specific protein DDB2, directly binds to UV−radiation−induced lesions and then stimulates the binding of XPC [Chu and Chang, 1988; Wakasugi et al., 2002; Scrima et al., 2008].”
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    • cites Scrima et al., 2008

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    Premisecitation

    XPC bound to the lesion becomes substrate for TFIIH, a ten-subunit complex that can switch functions in transcription initiation and NER.

    “XPC bound to the lesion becomes the substrate for the transcription initiation factor II H (TFIIH) complex, a transcription initiation and repair factor composed of ten protein subunits that can switch functions in both transcription initiation and in NER [Yokoi et al., 2000; Volker et al., 2001; Compe and Egly, 2012].”
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    • cites Compe and Egly, 2012

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    Premisecitation

    MMR is implicated in microsatellite stability, meiotic and mitotic recombination, DNA-damage signaling, apoptosis, class-switch recombination, somatic hypermutation, and triplet-repeat expansion.

    “MMR is also implicated in a variety of cellular processes including microsatellite stability, meiotic and mitotic recombination, DNA-damage signaling, apoptosis, class-switch recombination, somatic hypermutation and triplet-repeat expansion [Jiricny, 2006; Jiricny, 2013; Chatterjee et al., 2016a].”
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    • cites Jiricny, 2013

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    • cites Chatterjee et al., 2016a

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    Premisecitation

    Humans use MutSα (MSH2/MSH6) to recognize base mismatches and one-to-two nucleotide IDLs, and MutSβ (MSH2/MSH3) to recognize large IDLs.

    “Of the eight known MSH (MutS homolog) polypeptides in eukaryotes, humans employ the MutSα heterodimer (MSH2/MSH6) to recognize base mismatches and one-to-two nucleotide IDLs, and the MutSβ heterodimer (MSH2/MSH3) to recognize large IDLs [Kunkel and Erie, 2005; Sachadyn, 2010].”
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    • cites Sachadyn, 2010

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    Premisecitation

    Germline mutations in MMR genes result in Lynch syndrome, presenting as familial susceptibility to colon and ovarian cancers and other cancers.

    “Germline mutations in the MMR genes result in Lynch syndrome (also known as hereditary nonpolyposis colorectal cancer or HNPCC), which presents as a familial susceptibility to colon and ovarian cancers as well to a number of other cancers [Peltomaki, 2001].”
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    • cites Peltomaki, 2001

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    Premisecitation

    TC-NER is initiated by a lesion-stalled RNA polymerase II, which recruits CSA and CSB, essential for assembly of other TC-NER components.

    “The second NER pathway, TC-NER, is initiated by a lesion-stalled RNA polymerase II, which begins with the recruitment of TC−NER−specific proteins CSA (Cockayne syndrome WD repeat protein A; also known as ERCC8) and CSB (Cockayne syndrome protein B; also known as ERCC6), which are essential for additional assembly of other TC−NER components [Fousteri et al., 2006].”
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    • cites Fousteri et al., 2006

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    Premisecitation

    PARP1 is required for repair of single-strand breaks and damaged purine bases by a sub-pathway of BER.

    “In addition, PARP1 (Poly [ADP-ribose] polymerase 1) has also been shown to be required for the repair of single strand breaks and damaged purine bases by a sub-pathway of BER [Krokan and Bjoras, 2013; Reynolds et al., 2015].”
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    • cites Krokan and Bjoras, 2013

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    • cites Reynolds et al., 2015

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    Premisecitation

    An abasic site created by monofunctional glycosylases enters short-patch repair, while bifunctional glycosylases initiate long-patch BER.

    “An abasic site created from the monofunctional glycosylases gets committed to the short-patch-repair pathway, while the bifunctional glycosylases initiate the long-patch repair pathway of BER [Dianov and Hubscher, 2013].”
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    • cites Dianov and Hubscher, 2013

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    Premisecitation

    Proliferative status determines NER polymerase and ligase choice: POL ε predominates in non-replicating cells, POL δ and POL κ in replicating cells; LIG1-dependent ligation occurs in replicating cells, while XRCC1-LIG3 seals gaps in non-proliferating cells due to low dNTPs and LIG1.

    “Proliferative status of the cell determines the choice of polymerase used. For example, POL ε−dependent repair predominates in non−replicating cells, while POL δ and POL κ are the main NER polymerases in replicating cells. LIG1-dependent ligation occurs in replicating cells. However, XRCC1–LIG3 complex seals the gap in non-proliferating cells because of low expression of dNTPs and LIG1 in these”
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    • cites Moser et al., 2007

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    • cites Ogi et al., 2010

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    Premisecitation

    In long-patch BER, APE1 tailors the gap, POL β or POL δ/ε synthesize in a strand-displacement manner, flap endonuclease removes the flap, and LIG1 ligates.

    “In long patch repair, the repair gap left behind from the bifunctional glycosylase is tailored by the 3′ phosphodiesterase activity of APE1. Thereafter, POL β (in non-proliferating cells) or POL δ/ε (in proliferating cells) synthesize in a strand-displacement manner, which is then followed by flap removal by the flap endonuclease and a LIG1-mediated ligation [Akbari et al., 2009; Svilar et al., 2”
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    • cites Akbari et al., 2009

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    • cites Svilar et al., 2011

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    Premisenone given

    There are two major branches of NER: global genome NER and transcription-coupled NER.

    “There are two major branches of NER: global genome NER (GG−NER) and transcription−coupled NER (TC−NER).”
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  • May combine two claims.

    Premisecitation

    Mutations in POL β are found in solid cancers, and POL β variants can act as dominant negative and sequence-specific mutators.

    “Specifically, mutations in POL β are found in solid cancers and POL β variants can act as dominant negative and sequence specific mutators [Wang et al., 1992; Starcevic et al., 2004; Lang et al., 2007; Murphy et al., 2012].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Wang et al., 1992

      Not checked in the free run.

    • cites Starcevic et al., 2004

      Not checked in the free run.

    • cites Lang et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisenone given

    Once localized at the lesion, the CSA-CSB complex backtracks RNA polymerase II, exposing the lesion site, and TFIIH is recruited.

    “Once localized at the lesion site, the CSA-CSB complex backtracks (or reverse translocates) RNA polymerase II, exposing the lesion site. TFIIH is recruited to the lesion.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Typical MMR substrates are base mismatches arising during replication and insertion-deletion loops within repetitive DNA sequences from strand slippage.

    “Typical substrates for the MMR pathway are base mismatches that have arisen during replication and the insertion-deletion loops (IDLs) within repetitive DNA sequences that have resulted from strand slippage events [Errol C. Friedberg, 2005; Jiricny, 2006].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Errol C. Friedberg, 2005

      Not checked in the free run.

    • cites Jiricny, 2006

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MMR is an evolutionarily conserved post-replicative repair pathway that contributes to replication fidelity by at least 100-fold.

    “MMR is an evolutionarily conserved, post replicative repair pathway that contributes to replication fidelity by at least 100-fold [Kunkel, 2009; Arana and Kunkel, 2010].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Kunkel, 2009

      Not checked in the free run.

    • cites Arana and Kunkel, 2010

      Not checked in the free run.

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

    Premisecitation

    Mitochondria carry out both short- and long-patch BER, with synthesis by POL γ.

    “Finally, mitochondria are also known to carry out both short and long patch BER, where the synthesis step is carried out by POL γ; all of which adds to the significance of this repair pathway in the maintenance of global genome stability [Akbari et al., 2008; Liu and Demple, 2010].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Akbari et al., 2008

      Not checked in the free run.

    • cites Liu and Demple, 2010

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MutLα regulates termination of mismatch-provoked excision, and its endonuclease activity plays a role in 3′ nick-directed digestion by EXO1 in a PCNA/RFC-dependent manner.

    “MutLα regulates termination of mismatch-provoked excision, and its endonuclease activity plays a role in the 3′ nick-directed digestion by EXO1 (Exonuclease 1) in a PCNA/RFC dependent manner [Zhang et al., 2005; Kadyrov et al., 2006].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Zhang et al., 2005

      Not checked in the free run.

    • cites Kadyrov et al., 2006

      Not checked in the free run.

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

    Premisecitation

    Interstrand crosslinks are lesions in which two bases from complementary strands are covalently linked due to damage from crosslinking agents such as platinum compounds, nitrogen mustards, MMC, psoralens, and alkylating agents.

    “Interstrand crosslinks are lesions in which two bases from complementary strands are covalently linked due to damage to the DNA from crosslinking agents such as platinum compounds, nitrogen mustards, MMC, psoralens and alkylating agents [Clauson et al., 2013].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Clauson et al., 2013

      Not checked in the free run.

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

    Premisecitation

    FA disorder is a heterogeneous rare genetic disorder characterized by high frequency of hematological abnormalities, congenital anomalies, and general predisposition to cancers.

    “FA disorder is a heterogeneous and rare genetic disorder characterized with a high frequency of hematological abnormalities, congenital anomalies and a general predisposition to cancers [Kee and D’Andrea, 2012].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Kee and D’Andrea, 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Helix-distorting lesions are recognized by both GG-NER and TC-NER to initiate repair, although some lesions such as cisplatin may escape recognition.

    “Helix-distorting lesions are recognized by both the GG-NER and the TC-NER pathways to initiate repair, although some lesions such as cisplatin may escape recognition [Enoiu et al., 2012].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Enoiu et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    After lesion recognition in non-replicating cells, NER components cut only the 5′ side of the lesion, with further incisions possibly aided by MutSβ to create a ssDNA gap.

    “After lesion recognition, the components of the NER pathway are known to cut only the 5′ side of the lesion, with further incisions possibly aided by the MutSβ complex create a ssDNA-gap [Bessho et al., 1997; Mu et al., 2000; Smeaton et al., 2008; Zhao et al., 2009].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Bessho et al., 1997

      Not checked in the free run.

    • cites Mu et al., 2000

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    • cites Smeaton et al., 2008

      Not checked in the free run.

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

    Premisecitation

    The FA family consists of 21 functional complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V) known to suppress ICL sensitivity.

    “The FA family consists of 21 different functional complementation groups (A, B, C, D1, D2, E, F, G, I, J, L, M, N, O, P, Q, R, S, T, U, V), which are known to suppress ICL sensitivity [Bluteau et al., 2016; Michl et al., 2016].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bluteau et al., 2016

      Not checked in the free run.

    • cites Michl et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In non-replicating cells, error-prone TLS polymerase synthesizes across the gap, and a second round of NER removes the ICL hook on the other strand.

    “Next, the error-prone TLS polymerase synthesize across the gap and finally a second round of NER removes the ICL hook on the other strand [Clauson et al., 2013].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Clauson et al., 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Using a gapped plasmid assay, TLS is as high or higher in G2 compared to S phase in human cells, with slightly higher amounts of POL η in G2 compared to S phase.

    “Using a gapped plasmid assay, it has been shown that TLS is as high or higher in G2 compared to S phase in human cells, with slightly higher amounts of POL η in G2 compared to S phase of the cell cycle [Diamant et al., 2012].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Diamant et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Usually these gap-filling TLS events are expected to fall outside S phase, but cell-cycle independence is sometimes conferred based on the type of DNA lesion.

    “Usually, these type of TLS events are expected to fall outside of the S phase, but based on the type of DNA lesion, a cell-cycle independence is sometimes conferred [Quinet et al., 2016].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Quinet et al., 2016

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    An HSP90 inhibitor reduces expression of REV1 and POL η in human cells, indicating evolutionary regulation of these polymerases.

    “Likewise, an HSP90 inhibitor reduces expression of REV1 and POL η in human cells, indicating an evolutionary regulation of these polymerases [Sekimoto et al., 2010; Pozo et al., 2011].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sekimoto et al., 2010

      Not checked in the free run.

    • cites Pozo et al., 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    XPV patients lack POL η and are highly susceptible to UV radiation because alternate TLS polymerases POL ι and POL κ bypass UV-induced CPDs in an error-prone fashion.

    “These patients lack the POL η enzyme and are highly susceptible to UV radiation because alternate TLS polymerases (POL ι and POL κ) instead bypass the UV-induced cyclobutane dimers (CPD) in an error-prone fashion [Yamada et al., 2000; Sweasy et al., 2006; Wang et al., 2007b; Ziv et al., 2009].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Yamada et al., 2000

      Not checked in the free run.

    • cites Sweasy et al., 2006

      Not checked in the free run.

    • cites Wang et al., 2007b

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Incorrect nucleotides incorporated by TLS polymerases become mutations in the next round of replication, which propel tumorigenesis and disease but can also contribute to fitness and evolution of organisms.

    “If incorrect nucleotides were incorporated by TLS polymerases, they would become mutations in the next round of replication, which propel tumorigenesis and disease, but can also contribute to the overall fitness and evolution of organisms.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    REV1 orchestrates both insertion and extension by scaffolding TLS polymerases, binding an RIR-containing polymerase (POL η, POL ι, or POL κ) via one interface and POL ζ4 via a second interface.

    “The central molecule that orchestrates both the insertion and extension step is REV1, and by way of its unique scaffolding function facilitates an assemblage of the TLS polymerases by binding to an RIR-containing polymerase—POL η, POL ι, or POL κ—via one interface, and also to POL ζ4 (REV3-REV7-POLD2-POLD3), via a second interface, a central step in this model’s execution [Wojtaszek et al., 2012a;”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Wojtaszek et al., 2012a

      Not checked in the free run.

    • cites Wojtaszek et al., 2012b

      Not checked in the free run.

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

    Premisenone given

    Eleven TLS polymerases are known (REV1, POL η, POL ι, POL κ, POL ζ, POL μ, POL λ, POL β, POL ν, POL θ), distributed in four families (Y, B, X, A) and PrimPol.

    “A total of eleven TLS polymerases are known (REV1, POL η, POL ι, POL κ, POL ζ, POL μ, POL λ, POL β, POL ν, POL θ), which are distributed in four families (Y, B, X and A) and PrimPol (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisenone given

    TLS polymerases are required for ICL repair and can also play a role in BER and NER to synthesize new DNA after the excision step.

    “For instance, as previously discussed, TLS polymerases are required for ICL repair and can also play role in the BER and NER pathways to synthesize new DNA after the excision step.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisereasoning

    Although all TLS polymerases are less accurate than replicative polymerases, certain TLS polymerases can copy relatively accurately over certain cognate lesions.

    “Although all TLS polymerases are less accurate than replicative polymerases, certain TLS polymerases are able to copy relatively accurately over certain cognate lesions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Inhibition of NHEJ components alleviates sensitivity of FA-deficient cells to crosslinking agents, while the same cells show enrichment of 53BP1, RIF1, and RAP80 at damaged chromatin.

    “Similarly, inhibition of NHEJ components alleviates the sensitivity of FA deficient cells to crosslinking agents, while the same FA deficient cells show enrichment of 53BP1, RIF1 and RAP80 components at damaged chromatin [Adamo et al., 2010; Pace et al., 2010; Ceccaldi et al., 2016b; Renaud et al., 2016].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Adamo et al., 2010

      Not checked in the free run.

    • cites Pace et al., 2010

      Not checked in the free run.

    • cites Ceccaldi et al., 2016b

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    XPV patients exhibit a photosensitive phenotype with high incidence of skin cancer, highlighting the physiological significance of certain TLS polymerases bypassing particular lesions.

    “XPV patients, who exhibit a photosensitive phenotype with a high incidence of skin cancer, highlight the physiological significance of certain TLS DNA polymerases bypassing particular lesions.”
    Quote in the paperNot a substantial claim

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

    Premisenone given

    Cyclobutane thymine-thymine CPDs are cognate lesions for POL η.

    “For example, cyclobutane thymine-thymine CPDs are cognate lesions for POL η (Table 1).”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    REV1 is very important in mouse cells for synthesis across post-replicative gaps, where REV1 is recruited to the gaps by the 5′-end, unlike the gap-filling step of NER where POL κ is the polymerase of choice.

    “For example, REV1 is very important in mouse cells for synthesis across post-replicative gaps where REV1 gets recruited to the gaps by the 5′-end, unlike the gap-filling step of NER, where POL κ is the polymerase of choice [Ogi and Lehmann, 2006; de Groote et al., 2011; Sale, 2013].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Ogi and Lehmann, 2006

      Not checked in the free run.

    • cites de Groote et al., 2011

      Not checked in the free run.

    • cites Sale, 2013

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Once DNA-PKcs is recruited, it is activated in a DNA-dependent manner, pushes Ku inwardly on the DNA, and phosphorylates nearby components, including autoautophosphorylation.

    “However, once DNA-PKcs gets recruited, it is activated in a DNA dependent manner; it pushes Ku inwardly on the DNA and then phosphorylates other nearby components, including autoautophosphorylating itself [Gottlieb and Jackson, 1993; Yoo and Dynan, 1999; Weterings and Chen, 2008].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Gottlieb and Jackson, 1993

      Not checked in the free run.

    • cites Yoo and Dynan, 1999

      Not checked in the free run.

    • cites Weterings and Chen, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    These patients often manifest genetic instability and high incidence of cancers.

    “These patients often manifest genetic instability and high incidence of cancers [El-Khamisy et al., 2005; Reynolds et al., 2009].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites El-Khamisy et al., 2005

      Not checked in the free run.

    • cites Reynolds et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Activated ATM (from TIP60) phosphorylates H2AX, which serves as an anchor for MDC1.

    “Activated ATM (from TIP60) phosphorylates H2AX, which then serves as an anchor for MDC1 [Bhatti et al., 2011].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Bhatti et al., 2011

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    In long-patch SSBR, PARP1 detects SSBs and undergoes rapid poly(ADP)ribosylation and dissociation; end processing by APE1, PNKP, and APTX; FEN1 removes damaged 5′ termini aided by PARP1 and PCNA; POL β with POL δ/ε fills the gap; LIG1 ligates dependent on PCNA and XRCC1.

    “In the long patch SSBR pathway, SSBs are transiently detected by PARP1, which undergoes a rapid cycle of poly(ADP) ribosylation and dissociates to detect the next SSB [D’Amours et al., 1999; Davidovic et al., 2001]. After this, the ends undergo end processing by the apurinic-apyrimidic endonuclease 1 APE1, PNKP (polynuceotide kinase 3′-phosphate) and aprataxin (APTX) [McKinnon and Caldecott, 2007]”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites D’Amours et al., 1999

      Not checked in the free run.

    • cites Davidovic et al., 2001

      Not checked in the free run.

    • cites McKinnon and Caldecott, 2007

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S3 (load-bearing), S4 (based).

    Premisenone given

    SSBR is predicted to occur through three different pathways depending on the source of SSB.

    “SSBR is predicted to occur through three different pathways depending on the source of SSB.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    LIG4 joins the ends and completes NHEJ.

    “LIG4 joins the ends and completes the NHEJ process [Grawunder et al., 1997].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Grawunder et al., 1997

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Chromatin modification is the first event that registers a DSB and triggers a cascade including ATM activation, H2AX phosphorylation, chromatin PARylation, MDC1 recruitment, and recruitment of 53BP1 and BRCA1.

    “Chromatin modification is the first event that registers the presence of a DSB and triggers a cascade of events including ATM activation, targeted phosphorylation of H2AX, chromatin PARylation, MDC1 recruitment and finally recruitment of 53BP1 and BRCA1 [Rogakou et al., 1998; Rothkamm et al., 2003; Gottschalk et al., 2009; Chou et al., 2010; Lukas et al., 2011; Price and D’Andrea, 2013; Liu et al”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Rogakou et al., 1998

      Not checked in the free run.

    • cites Rothkamm et al., 2003

      Not checked in the free run.

    • cites Gottschalk et al., 2009

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In short-patch SSBR, SSBs generated during BER are recognized by APE1 followed by similar end-processing; gap filling is only by POL β, followed by LIG3-catalyzed ligation.

    “In the short patch SSBR pathway, SSBs generated during the BER are recognized by APE1 followed by a similar end-processing pathway as the long patch repair. The gap-filling step, however, is only carried out by POL β enzyme, followed by LIG3-catalyzed ligation [McKinnon and Caldecott, 2007].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites McKinnon and Caldecott, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    MDC1 is phosphorylated by ATM, and phosphorylated MDC1 functions as a scaffold to bring in ubiquitin E3 ligases RNF8 and RNF168.

    “Next, MDC1 is phosphorylated by ATM, and the phosphorylated MDC1 functions as a scaffold to bring in the ubiquitin E3 ligases RNF8 and RNF168 [Altmeyer and Lukas, 2013b].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Altmeyer and Lukas, 2013b

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In S/G2 phase where HR is predominant, BRCA1 recruited by ubiquitinated chromatin counteracts 53BP1 and initiates ubiquitination of CtIP.

    “In the S/G2 phase where HR is predominant, BRCA1 (recruited by ubiquitinated chromatin) successfully counteracts 53BP1 and initiates ubiquitination of the downstream component, CtIP [Yu et al., 2006; Chapman et al., 2012].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Yu et al., 2006

      Not checked in the free run.

    • cites Chapman et al., 2012

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The Ku heterodimer (Ku70 and Ku80) is the first to recognize and bind DSBs within seconds to prevent end resection and serves as a scaffold to recruit other NHEJ components.

    “The Ku (Ku70 and Ku80) heterodimer is the first to recognize and bind the DSBs within seconds to prevent end resection and serves as a scaffold to recruit other NHEJ components [Pang et al., 1997; Mari et al., 2006; Soutoglou et al., 2007; Mimitou and Symington, 2010].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Pang et al., 1997

      Not checked in the free run.

    • cites Mari et al., 2006

      Not checked in the free run.

    • cites Soutoglou et al., 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Unresolved SSBs collapse DNA replication, stall ongoing transcription, and effect PARP1 activation, which releases cellular NAD+, ATP, and apoptosis inducing factor.

    “Unresolved SSBs often collapse DNA replication, stall ongoing transcription, and effect PARP1 activation, which releases cellular NAD+, ATP and apoptosis inducing factor (AIF) in cells [Zhou and Doetsch, 1993; Heeres and Hergenrother, 2007]”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Zhou and Doetsch, 1993

      Not checked in the free run.

    • cites Heeres and Hergenrother, 2007

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    53BP1 and BRCA1 exhibit antagonistic influence on each other, and 53BP1 depletion rescues embryonic lethality of BRCA1 null mice.

    “Interestingly, both 53BP1 and BRCA1 exhibit an antagonistic influence on each other and 53BP1 depletion rescues embryonic lethality of BRCA1 null mice [Xie et al., 2007; Cao et al., 2009; Bunting et al., 2010].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Xie et al., 2007

      Not checked in the free run.

    • cites Cao et al., 2009

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    • cites Bunting et al., 2010

      Not checked in the free run.

  • May combine two claims.

    Premisereasoning

    Both RNF8 and RNF168 ubiquitinate H2AX, which serves as a docking site for 53BP1 and BRCA1.

    “Both of these E3 ligases ubiquitinate H2AX, which then serves as a docking site for 53BP1 and BRCA1.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    The MRN complex initiates HR at a DSB by recognizing and binding the DSB and recruiting ATM and TIP60.

    “The MRN (MRE11-RAD50-NBS1) complex initiates HR at a DSB, where it recognizes and binds the DSB and then recruits ATM and TIP60 to the DNA [Sun et al., 2005; Stracker and Petrini, 2011].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Sun et al., 2005

      Not checked in the free run.

    • cites Stracker and Petrini, 2011

      Not checked in the free run.

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

    Premisecitation

    Unresolved DSBs are implicated in various human disorders and cancers.

    “Unresolved DSBs are implicated in various human disorders and cancers [Jackson and Bartek, 2009].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Jackson and Bartek, 2009

      Not checked in the free run.

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

    Premisecitation

    In addition to traditional DSBR-induced HR, synthesis-dependent strand annealing and break-induced repair are variations following the HR premise.

    “In addition to the traditional DSBR-induced HR pathway, synthesis-dependent strand annealing (SDSA) and break-induced repair (BIR) are two other variations following the HR premise [Li and Heyer, 2008].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Li and Heyer, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Recent studies indicate that the order of recruitment of NHEJ components may depend on the complexity of DNA damage; for instance, DNA-PKcs recruitment depends on the nature of the break.

    “Recent studies indicate that the order of recruitment of these components may depend on the complexity of DNA damage; for instance, DNA-PKcs recruitment depends on the nature of the break [Mari et al., 2006; Yano and Chen, 2008].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Mari et al., 2006

      Not checked in the free run.

    • cites Yano and Chen, 2008

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In NHEJ, 53BP1 recruits NHEJ components to the break site, activates checkpoint signaling, and facilitates synapsis of the two ends.

    “In the NHEJ pathway of DSBR, 53BP1 plays an important regulatory role by recruiting the NHEJ components to the break site, activating checkpoint signaling and facilitating synapsis of the two ends [Panier and Boulton, 2014].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Panier and Boulton, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Short telomeres frequently form telomere dysfunction-induced foci containing 53BP1, ATM, γH2AX, and MRE11, and these foci are highly susceptible to NHEJ-mediated end-to-end fusion.

    “For example, short telomeres often assemble DDR factors such as 53BP1, ATM, γH2AX, and MRE11 as foci, called Telomere Dysfunction-Induced Foci (TIF), which are highly prone to NHEJ-mediated end-to-end fusion [Takai et al., 2003; Hewitt et al., 2012; Marcand, 2014].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Takai et al., 2003

      Not checked in the free run.

    • cites Hewitt et al., 2012

      Not checked in the free run.

    • cites Marcand, 2014

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Telomerase, a ribonucleoprotein containing TERC and TERT, maintains telomeric DNA and is the sole positive regulator of telomere length.

    “In addition, telomeric DNA is replicated and maintained by a specialized ribonucleoprotein complex called telomerase [composed of a telomere RNA component (TERC) and a telomere reverse transcriptase (TERT)], which is the only positive regulator of telomere length [Bachand et al., 2001; Blasco, 2003].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Bachand et al., 2001

      Not checked in the free run.

    • cites Blasco, 2003

      Not checked in the free run.

  • May combine two claims. The quote only partly states this claim.

    Premisecitation

    During homologous recombination, resection of DNA ends proceeds in a 5′-to-3′ direction, producing 3′ overhangs and committing the cell to HR.

    “Initial resection occurs by the endonuclease activity of MRN, with the help of CtIP, followed by long-range resection by EXO1 or BLM together with DNA2 [Chen et al., 2008; Nimonkar et al., 2011].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Chen et al., 2008

      Not checked in the free run.

    • cites Nimonkar et al., 2011

      Not checked in the free run.

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

    Premisenone given

    Other HR components RPA and RAD51 make their way onto the DNA.

    “At this time, the other HR components, RPA, and RAD51 proteins make their way on to the DNA.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BRCA2 and PALB2 promote assembly of the RAD51 nucleoprotein filament, which invades a nearby duplex DNA and forms a D-loop.

    “BRCA2 and PALB2 aid in the formation of the nucleoprotein filament formation that invades a nearby duplex DNA forming a D-loop [Zhang et al., 2009; Holloman, 2011].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Zhang et al., 2009

      Not checked in the free run.

    • cites Holloman, 2011

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Decreased telomerase activity contributes to telomere attrition, which is linked to aging, cancer, and several inherited bone marrow failure disorders.

    “A decline in telomerase activity contributes to telomere attrition, which is associated with aging, cancer and several inherited bone marrow failure (IBMF) disorders [Chang and Harley, 1995; Shay et al., 2001; Alter et al., 2015].”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites Chang and Harley, 1995

      Not checked in the free run.

    • cites Shay et al., 2001

      Not checked in the free run.

    • cites Alter et al., 2015

      Not checked in the free run.

  • Probably not a substantial claim: may not pass S4 (based).

    Interpretationnone given

    DNA is continuously exposed to endogenous and exogenous damaging agents that chemically modify its constituents.

    “In conclusion, DNA is continually being exposed to both endogenous and exogenous DNA damaging agents that chemically modify the DNA constituents.”
    Quote in the paperNot a substantial claim
91 of 91

  • The paper relies on this without support.

    Living organisms are continuously exposed to DNA-damaging agents that can affect health and modulate disease states.

    “Living organisms are continuously exposed to a myriad of DNA damaging agents that can impact health and modulate disease-states.”

  • The paper relies on this without support.

    Aging is attributed to attrition of chromosomal ends and failing capacities of a combination of DNA repair and tolerance pathways.

    “Likewise, aging is attributed to attrition of chromosomal ends and failing capacities of a combination of these pathways.”

  • The paper relies on this without support.

    Neurodegenerative disorders result from combinatorial failure of more than one DNA repair or tolerance process.

    “Other diseases, such as neurodegenerative disorders, result from a combinatorial failure of more than one of these processes.”

  • The paper relies on this without support.

    Routinely used biological, physical, and chemical agents impact human health.

    “Because routinely used biological, physical and chemical agents impact human health, testing their genotoxicity and regulating their use have become important.”
4 of 4

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Intact DNA repair machinery in primary cells efficiently corrects replication errors and DNA damage prior to cell division, ensuring accurate chromosomal segregation and preserving genomic integrity.

    “This intact repair machinery efficiently corrects replication errors and DNA damage prior to cell division, ensuring accurate chromosomal segregation and preserving overall genomic integrity”

    From Primary cell cultures versus immortalized cell lines: critical comparative insights into biological fidelity and translational applications (2026) · cites this paper as Chatterjee and Walker 2017

    The Introduction (page not provided) says DNA repair pathways remove damage during the cell cycle and help maintain genetic stability. The replication-errors section (page not provided) says mismatch repair corrects errors that escape proofreading. The paper does not establish this specifically for primary cells or say that repair ensures accurate chromosomal segregation before division; it also acknowledges that some errors persist. (LLM, conf=0.86)

    Experimental — accuracy not yet measured

  • In GG-NER, damage is recognized by XPC working with RAD23B and CETN2.

    “In GG-NER, damage is recognized by the XPC protein working in concert with the UV excision repair protein RAD23 homolog B (RAD23B) and centrin 2 (CETN2) [23].”

    From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [23]

  • The main function of the XPC-RAD23B-CETN2 complex is DNA scanning in search of helix destabilization.

    “The main function of the formed complex is DNA scanning in search of helix destabilization.”

    From Focus on UV-Induced DNA Damage and Repair—Disease Relevance and Protective Strategies (2020) · cites this paper as [23]

Cites

2 retracted

Flagged first, then by citations

5 of the 495 references couldn’t be matched to a known paper.

Research works printed but not linked: 2

  1. Naegeli H., 1997, DNA structure: Inherent instability and genomic reactions
  2. Tropp BE., 2011, Molecular biology, from Gene to Protein, 1100

Cited by

Sorted by citations

Related

Authors
Chatterjee, N., & Walker, G. C.
Affiliations
Massachusetts Institute of Technology (US)
Corresponding author
Chatterjee, Nimrat
ORCID
Venue
Environmental and Molecular Mutagenesis
Publisher
Wiley
Published
2017-05-09
Volume
58
Issue
5
Pages
235-263
ISSN
  • 0893-6692 (ISSN-L)
  • 1098-2280
DOI
10.1002/em.22087
PMC
PMC5474181
OpenAlex
W2612428976
Cited by
2,039
References
495
Citations by year
2026: 165 · 2025: 315 · 2024: 328 · 2023: 344 · 2022: 306 · 2021: 286 · 2020: 185 · 2019: 66 · 2018: 31 · 2017: 10 · 2016: 1
FWCI
7.44
Type
journal article
Language
en
Open access
Licence
onlinelibrary.wiley.com/termsAndConditions#vor (vor)
Locations
  • Environmental and Molecular Mutagenesis (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc-sa)
  • PMC
Funders
National Institute of Environmental Health Sciences (ES‐015818)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Carcinogens and Genotoxicity Assessment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA and Nucleic Acid Chemistry
Keywords
DNA damage, DNA repair, mutagenesis, genotoxicity, genomic instability, DNA damage tolerance, DNA repair pathways, cancer, chemical carcinogens, physical carcinogens
MeSH terms
Animals, DNA Damage, DNA Repair, Humans, Mutagenesis, Telomere

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.

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