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Cited by 1,966DNA Repair MechanismsCancer-related Molecular PathwaysProtein Kinase Regulation and GTPase Signaling

Cell cycle checkpoint signaling through the ATM and ATR kinases

Open access
Abraham, Robert T.·2001·Genes & Development
DOI 10.1101/gad.914401
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Abstract

The genomes of eukaryotic cells are under continuous assault by environmental agents (e.g., UV light and reactive chemicals) as well as the byproducts of normal intracellular metabolism (e.g., reactive oxygen intermediates and inaccurately replicated DNA).Whatever the origin, genetic damage threatens cell survival, and, in metazoans, leads to organ failure, immunodeficiency, cancer, and other pathologic sequelae.

AI snapshot

Written from the paper’s full text.

TL;DR

This review synthesizes the roles of ATM and ATR, two phosphoinositide 3-kinase-related kinases, in DNA damage and cell-cycle checkpoint signaling. It argues that ATM primarily handles ionizing radiation-induced double-strand breaks, while ATR is more central to replication stress, UV damage, and S/G2 checkpoint responses.

Key findings

  • ATM and ATR are S/T-Q-directed protein kinases; ATM activity increases several-fold within 1 h after ionizing radiation or radiomimetic treatment, whereas ATR did not show such activation in immune-complex assays but redistributes into nuclear foci after DNA damage.
  • ATM and ATR phosphorylate overlapping substrates, including p53 at Ser15, MDM2 at Ser395, Chk2 at Thr68, p53 at Ser20 via Chk2, Cdc25A at Ser123 via Chk2, NBS1 at Ser343/Ser397/Ser615, and BRCA1 within its SQ cluster domain, which contains 14 S-Q motifs, 10 in an ~300-amino-acid region (residues 1250–1550), with major IR-induced sites at Ser1387, Ser1423, and Ser1524.
  • In S phase, the ATM-Chk2-Cdc25A pathway suppresses radioresistant DNA synthesis; ATR is proposed to govern a parallel replication-stress pathway, and ATR phosphorylates six Ser/Thr residues in the BRCA1 carboxyl terminus.
  • In G2, ATR-Chk1 signaling is implicated when damage occurs before S phase completion, while ATM is required when damage occurs during G2 itself; Chk1−/− embryonic stem cells show reduced G2 arrest after IR, and Chk2−/− cells show a maintenance defect.
  • Extranuclear ATM is linked to insulin/IGF signaling, including phosphorylation of PHAS-I/4E-BP1 at Ser111 and regulation of IGF-1 receptor expression.

Methods

  • Narrative review, not a primary experimental study; it synthesizes published literature on mammalian ATM and ATR checkpoint signaling, with brief references to yeast and Xenopus model systems.
  • Evidence base consists of cited studies; the article cites 145 references, 77 of which are noted as freely accessible.
  • Main analysis is conceptual and mechanistic, organized around PIKK family structure, ATM/ATR biochemistry, associated complexes such as BASC, G1/S/G2 checkpoint functions, extranuclear ATM roles, and therapeutic implications.

Limitations

  • The paper states that understanding of DNA damage sensors and the mechanisms that initiate and terminate checkpoint activation remains skeletal; DNA-dependent activation of ATM/ATR is controversial, with opposite results across laboratories; ATR activation was not detected in whole-cell extracts; and definitive tests await an ATR-deficient cell line with an intact G1 checkpoint.
  • Evident from the text: this is a review without systematic search or new data, many conclusions rest on in vitro immune-complex kinase assays with millimolar Mn2+ and detergent-sensitive ATM activity, and some cited findings are in press or unpublished; proposed therapeutic uses of ATM/ATR inhibitors are speculative.

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

Integrity signals

Registry

Crossref · 10.1101/gad.914401

Cites

151 of 151 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 119 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Under the same experimental conditions, ATM did not enter nuclear foci in cells damaged by ionizing radiation or other DNA-damaging agents.

    “Under identical experimental conditions, ATM did not enter into nuclear foci in cells damaged with IR or other DNA-damaging agents.”
    Quote in the paperSubstantial claim
  • Findingcitation

    A GST-hRad17 fusion protein is a significantly better substrate for ATR than for ATM.

    “A peptide containing these sites was phosphorylated at a higher rate by ATR than by ATM (Kim et al. 1999), and we have found that a GST-hRad17 fusion protein is a significantly better substrate for ATR than for ATM (Bao et al. 2001; R.S. Tibbetts and R.T. Abraham, unpubl.).”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Bao et al. 2001

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    • cites R.S. Tibbetts and R.T. Abraham, unpubl.

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  • Findingcitation

    ATR in vitro kinase activity does not increase after cells are treated with various genotoxic agents, including ionizing radiation and UV light.

    “On the other hand, our group has failed to detect any increases in the in vitro kinase activity of ATR after treatment of cells with various genotoxic agents, including IR and UV light (R.S. Tibbetts and R.T. Abraham, unpubl.).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites R.S. Tibbetts and R.T. Abraham, unpubl.

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  • Findingreasoning

    When this ATM-dependent pathway is disrupted, cells show radioresistant DNA synthesis.

    “Disruption of this pathway yields the radioresistant DNA synthesis (RDS) phenotype.”
    Quote in the paperSubstantial claim
  • Findingown data

    ATM and ATR share a functionally undefined region of homology at their amino termini.

    “The amino-terminal cross-hatched box indicates a functionally undefined region of homology between ATM (residues 1493-1773) and ATR (residues 1191-1463).”
    Quote in the paperNot a substantial claim
  • May combine two claims. 33
  • Classified as probably not a substantial claim. 1

  • May combine two claims.

    Findingown data

    hSMG1 localizes to both the nucleus and cytoplasm and, like ATM and ATR, phosphorylates proteins containing Ser-Gln motifs in vitro.

    “Our own results indicate that hSMG1 is found in both the nucleus and cytoplasm, and, like ATM and ATR, exhibits phosphotransferase activity toward a variety of proteins containing Ser-Gln motifs under in vitro assay conditions.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation
    § Cell cycle checkpoint signaling through the ATM and ATR kinases

    Rad family checkpoint proteins, including Rad17, Rad1, Rad9, Rad26, and Hus1, are expressed widely in eukaryotic cells and are leading candidates for DNA damage sensors.

    “However, members of the Rad group of checkpoint proteins, which include Rad17, Rad1, Rad9, Rad26, and Hus1 (nomenclature based on the Schizosaccharomyces pombe gene products) are widely expressed in all eukaryotic cells, and are prime suspects in the lineup of candidate DNA damage sensors (Green et al. 2000;O'Connell et al. 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Green et al. 2000

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    • cites O'Connell et al. 2000

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  • May combine two claims.

    Premisecitation

    mTOR coordinates G1 phase progression with nutrient and growth factor availability and has no identified role in genome surveillance.

    “On the other hand, mTOR plays no identifiable role in genome surveillance; rather, this PIKK coordinates G 1 phase progression with the supply of nutrients and growth factors (Gingras et al. 2001).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Gingras et al. 2001

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  • May combine two claims.

    Premisecitation

    DNA-PKcs acts as a heterotrimeric complex with Ku70 and Ku80 and contributes to genome maintenance through nonhomologous end joining of DNA double-strand breaks.

    “The catalytic subunit of DNA-dependent protein kinase (DNA-PK cs ) functions as a heterotrimeric complex containing two Ku subunits (Ku-70 and Ku-80), and makes its own crucial contribution to genome maintenance by overseeing the nonhomologous end-joining (NHEJ) pathway of DNA double-strand break (dsb) repair (Smith and Jackson 1999).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Smith and Jackson 1999

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    Premisecitation
    § Cell cycle checkpoint signaling through the ATM and ATR kinases

    Rad17 is homologous to RFC subunits and associates with RFC subunits to form a putative checkpoint clamp loading complex that controls the interaction of the Rad1-Rad9-Hus1 complex with damaged DNA.

    “Interestingly, yet another member of the Rad family, Rad17, bears homology to the RFC subunits and, in fact, associates with RFC subunits to form a putative checkpoint clamp loading complex (CLC) that governs the interaction of the Rad1-Rad9-Hus1 CSC with damaged DNA (Green et al. 2000;O'Connell et al. 2000).”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Green et al. 2000

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    • cites O'Connell et al. 2000

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  • May combine two claims.

    Premisecitation
    § Cell cycle checkpoint signaling through the ATM and ATR kinases

    Rad1, Rad9, and Hus1 resemble PCNA structurally, and evidence supports that this resemblance may also extend to function.

    “Three of these Rad proteins, Rad1, Rad9, and Hus1, exhibit structural similarity to the proliferating cell nuclear antigen (PCNA), and accumulating evidence supports the idea that this similarity may extend to function as well (Thelen et al. 1999;Burtelow et al. 2000).”
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    • cites Thelen et al. 1999

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    • cites Burtelow et al. 2000

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  • May combine two claims.

    Premisecitation

    ATM and ATR show S/T-Q-directed kinase activity in vitro, and p53 is a physiologically relevant substrate for both kinases.

    “Immune complex kinase assays quickly revealed that, like DNA-PK, ATM and ATR displayed S/T-Q-directed kinase activities under in vitro conditions, and that a physiologically relevant substrate for both protein kinases was p53 (Banin et al. 1998;Canman et al. 1998;Tibbetts et al. 1999;Ziv et al. 2000).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Banin et al. 1998

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    • cites Canman et al. 1998

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    • cites Tibbetts et al. 1999

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  • May combine two claims.

    Interpretationreasoning

    ATM and ATR respond to DNA damage in fundamentally different ways: ATM becomes catalytically active, whereas ATR redistributes into DNA damage-induced nuclear foci.

    “Collectively, these results hint that ATM and ATR respond to DNA damage in fundamentally different fashions: One checkpoint kinase (ATM) becomes catalytically active, whereas the other (ATR) redistributes into DNA damage-induced nuclear foci, where it presumably gains access to its substrates.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    The consensus phosphorylation site for ATM is (M/F)-(Q/P)-L-S-Q-(E/Q), with a core L-S-Q-E sequence identical to that around p53 Ser15.

    “These efforts identified a consensus phosphorylation site [(M/F)-(Q/P)-L-S-Q-(E/Q)] that was in reasonable agreement with that defined by Kastan and coworkers (Kim et al. 1999).Remarkably, the relatively unbiased peptide selection strategy zeroed in on a core L-S-Q-E target sequence, which was identical to that surrounding the Ser 15 site in p53.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites O'Neill et al. 2000

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    • cites Kim et al. 1999

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  • May combine two claims.

    Premisecitation

    Loss of NBS1 causes Nijmegen breakage syndrome, a chromosomal instability disorder with similarities to ataxia-telangiectasia.

    “The latter complex plays impor-tant roles in the recombinational repair of DNA dsbs, and the loss of one of the components of this complex, NBS1, gives rise to the Nijmegen breakage syndrome, a chromosomal instability disorder that bears several similarities to A-T (Shiloh 1997).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Shiloh 1997

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  • May combine two claims.

    Premisecitation

    Many DNA damage-induced nuclear foci react with both ATR- and BRCA1-specific antibodies, suggesting that ATR and BRCA1 colocalize at DNA damage sites.

    “Many of these foci react with both ATR-and BRCA1-specific antibodies, suggesting that the two proteins colocalize at sites of DNA damage.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites Scully et al. 1997

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    • cites Tibbetts et al. 2000

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  • May combine two claims.

    Premisecitation

    BRCA1 is a critical component of checkpoint signaling and DNA repair and is directly phosphorylated by ATM and ATR after genotoxic stress.

    “The breast cancer susceptibility protein, BRCA1, is a critical component of the checkpoint signaling and DNA repair machinery, and is a direct target for phosphorylation by ATM and ATR in cells exposed to genotoxic stress (Cortez et al. 1999;Scully and Livingston 2000;Scully et al. 2000;Tibbetts et al. 2000).”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Cortez et al. 1999

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    • cites Scully and Livingston 2000

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    • cites Tibbetts et al. 2000

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  • May combine two claims.

    Premisecitation

    In cells overexpressing kinase-inactive ATR, the early phase of IR-induced p53 phosphorylation is not impaired, consistent with ATM being the major Ser15 kinase during the acute IR response.

    “In cells rendered functionally deficient for ATR by overexpression of a kinase-inactive ATR KI mutant (Cliby et al. 1998), the early phase (0-2 h) of IR-induced p53 phosphorylation was not impaired, which is consistent with the idea that ATM serves as the major Ser 15 kinase during the acute response to IR”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tibbetts et al. 1999

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  • May combine two claims.

    Premisecitation

    Ionizing radiation rapidly induces p53 Ser15 phosphorylation in cells, and this response is ATM-dependent, being significantly but not completely suppressed in A-T cells.

    “Moreover, phosphorylation of Ser 15 was rapidly induced in IR-treated cells, and this response was ATM dependent, as IR-induced Ser 15 phosphorylation was significantly, but not completely, suppressed in A-T cells”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Siliciano et al. 1997

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    • cites Banin et al. 1998

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    • cites Canman et al. 1998

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  • May combine two claims.

    Premisecitation

    ATR KI-overexpressing cells have a significant defect in maintaining Ser15 phosphorylation at later times, suggesting that the maintenance phase depends more on ATR.

    “However, the ATR KI -overexpressing cells did show a significant defect in their ability to maintain phosphorylation of Ser 15 at later times, which suggests that the maintenance phase of p53 phosphorylation was more highly dependent on ATR.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tibbetts et al. 1999

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  • May combine two claims.

    Premisecitation

    UV light triggers p53 Ser15 phosphorylation that is largely independent of ATM and strongly reduced at all times by ATR KI overexpression.

    “On the other hand, treatment of human fibroblasts with UV light triggered a Ser 15 phosphorylation response that was largely independent of ATM expression, and was strongly reduced, at all times postirradiation, by overexpression of ATR KI”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Tibbetts et al. 1999

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  • May combine two claims.

    Premisecitation

    Ser15 phosphorylation is not sufficient to disrupt p53-MDM2 binding; instead it stimulates p53 transactivation by enhancing p300 binding.

    “It turns out, however, that Ser 15 phosphorylation is not sufficient to disrupt the p53-MDM2 interaction; rather, this modification stimulates the transactivating function of p53 by enhancing the binding of this protein to the transcriptional coactivator, p300”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Dumaz and Meek 1999

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  • May combine two claims.

    Interpretationreasoning

    When ATM is absent or IR damage is high, ATR acts mainly as a backup kinase for ATM.

    “In the absence of ATM, or in normal cells that incur a high level of IR-induced DNA damage, ATR serves mainly as a backup kinase for ATM.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    p53 Ser20 phosphorylation directly interferes with p53-MDM2 binding, favoring p53 accumulation after IR-induced DNA damage.

    “Unlike the Ser 15 modification mentioned earlier, phosphorylation at Ser 20 interferes directly with the binding of p53 to MDM2, thereby favoring p53 accumulation in response to IR-induced DNA damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    In the absence of ATM, the IR-induced decrease in DNA synthesis is significantly dampened, producing the RDS phenotype.

    “In the absence of ATM, the IR-induced decrease in DNA synthesis is dampened significantly, giving rise to the RDS phenotype.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Painter and Young 1980

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  • May combine two claims.

    Interpretationcitation

    Mutant hChk2 alleles associated with variant Li-Fraumeni syndrome fail to bind and/or phosphorylate Cdc25A, implying that genetic lesions in the RDS pathway promote genome instability and cancer.

    “Remarkably, mutant hChk2 alleles associated with a variant form of Li-Fraumeni syndrome (Bell et al. 1999) failed to bind and/or phosphorylate Cdc25A (Falck et al. 2001), which implies that genetic lesions in the RDS pathway promote genome instability and cancer development.”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites Falck et al. 2001

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    • cites Bell et al. 1999

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  • May combine two claims.

    Premisecitation

    hChk2 phosphorylates Ser123 in Cdc25A, targeting Cdc25A for ubiquitin-dependent degradation.

    “The results obtained by Falck et al. (2001) show that hChk2 phosphorylates Ser 123 in Cdc25A, and that this modification targets Cdc25A for ubiquitin-dependent degradation.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Falck et al. 2001

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  • May combine two claims.

    Premisecitation

    NBS1-Mre11-Rad50 focus appearance depends on NBS1 expression, and the absence of major DNA repair defects in NBS cells indicates that Mre11-Rad50 repairs capably in NBS1-deficient cells.

    “The appearance of these foci is dependent on the expression of NBS1; however, the absence of major DNA repair defects in cells from NBS patients indicates that the Mre11-Rad50 complex carries out its repair functions quite capably in NBS1-deficient cells”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Petrini 1999

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  • May combine two claims.

    Premisecitation

    ATM phosphorylates NBS1 on up to three serine residues, and Ser-to-Ala substitution at any one of these sites generates a mutant NBS1 that fails to complement checkpoint defects in NBS cells.

    “ATM phosphorylates NBS1 on up to three serine residues (Ser 343, Ser 397, and Ser 615), and that Ser → Ala substitutions at any one of these sites generated a mutant NBS1 protein that failed to complement the checkpoint defects in NBS cells”
    Quote in the paperSubstantial claim0 of 3 sources checked
    • cites Gatei et al. 2000b

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    • cites Lim et al. 2000

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    • cites Wu et al. 2000

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  • May combine two claims.

    Premisecitation

    IR induces rapid nuclear foci containing the NBS1-Mre11-Rad50 complex, and these foci assemble close to DNA double-strand breaks.

    “Treatment of cells with IR induces the rapid formation of nuclear foci containing the NBS1-Mre11-Rad50 complex, and a technologically elegant study offered strong evidence that the foci assemble in close proximity to DNA dsbs”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Nelms et al. 1998

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  • May combine two claims.

    Interpretationown data

    With the caveat that overexpressed ATR KI may cross-inhibit ATM, the results suggest either that ATR also acts upstream of hChk2 or that ATR regulates a parallel pathway suppressing DNA synthesis in IR-damaged cells.

    “With the caveat in mind that overexpressed ATR KI may nonspecifically cross-inhibit ATM function, these results suggest either that ATR also resides upstream of hChk2, or that ATR regulates a parallel pathway that contributes to the suppression of DNA synthesis in IR-damaged cells.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    NBS cells display the RDS phenotype, suggesting that NBS1 is an upstream regulator of Cdc25A stability in IR-treated cells.

    “Interestingly, NBS cells also display the RDS phenotype, which suggests that the NBS1 protein is an upstream regulator of Cdc25A stability in IR-treated cells.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    BRCA1 phosphorylation in IR-damaged cells is significantly impaired without ATM, and at least five S-Q sites in the SCD are phosphorylated by ATM in vitro.

    “Cortez et al. (1999) observed that the phosphorylation of BRCA1 in IR-damaged cells was significantly impaired in the absence of ATM, and demonstrated that at least five of the predicted S-Q target sites in the SCD were phosphorylated by ATM in vitro.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites Cortez et al. 1999

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    Premisecitation

    The BRCA1 carboxy-terminal region contains 14 S-Q motifs, 10 of which lie in the SQ cluster domain spanning residues 1250-1550.

    “The carboxy-terminal region of BRCA1 contains numerous S-Q motifs (total of 14), and, of these potential ATM/ATR target sequences, 10 are localized in an ∼300 amino acid stretch (residues 1250-1550) termed the SQ cluster domain (SCD)”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites Cortez et al. 1999

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  • May combine two claims.

    Interpretationnone given

    ATM is specialized for a fast protective reaction to DNA double-strand breaks, whereas ATR is not.

    “In contrast to ATR, ATM seems dedicated to providing the cell with a rapid protective response to an extremely lethal form of DNA damage, the DNA dsb.”
    Quote in the paperSubstantial claim

  • Probably not a substantial claim: may not pass S2 (checkable), S4 (based).

    Interpretationnone given

    Evolutionary pressure from oxygen-derived radicals and the need to generate diverse antigen-responsive lymphocytes likely drove development of a checkpoint signaling module for detecting DNA double-strand breaks.

    “it is likely that, outside of the laboratory setting, the intrinsic accoutrements of life as a multicellular organism, such as continuous assaults by oxygen-derived radicals, and the need to generate a diverse repertoire of antigen-responsive lymphocytes, generated evolutionary pressure for the development of a checkpoint signaling module geared toward sounding the DNA dsb alarm at the first sign”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Interpretationnone given

    This pathway might employ Rad family proteins both to sense damage and to serve as scaffolds that assemble signaling complexes.

    “The pathway is governed primarily by ATR, and may use members of the Rad family of checkpoint proteins as damage sensors and as scaffolds for the assembly of checkpoint signaling complexes.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    As a result, cyclin•cdk2 complexes cannot stay active and DNA synthesis is inhibited.

    “The checkpoint response leads to the proteosome-mediated degradation of Cdc25A, and, in turn, the failure to maintain activation of cyclin•cdk2 complexes and a resultant inhibition of DNA synthesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisereasoning

    The two branches meet at Cdc25C; they block activation of the mitotic cyclin B•cdc2 complex by sequestering Cdc25C in the cytoplasm and/or inhibiting its catalytic activity.

    “Both branches converge on the Cdc25C phosphatase, and prevent activation of the mitotic cyclin B•cdc2 complex by inducing the cytoplasmic sequestration and/or catalytic inhibition of Cdc25C.”
    Quote in the paperSubstantial claim
34 of 34

  • The paper relies on this without support.

    Cell-cycle checkpoints detect damaged or abnormally structured DNA and coordinate cell-cycle progression with DNA repair.

    “The overall function of these checkpoints is to detect damaged or abnormally structured DNA, and to coordinate cell-cycle progression with DNA repair.”

  • The paper relies on this without support.

    In mammalian cells, ATM and ATR play critical roles in early signal transmission through cell-cycle checkpoints.

    “In mammalian cells, two PIKK family members, ATM (ataxia-telangiectasia mutated) and ATR (ATM and Rad 3-related), play critical roles in early signal transmission through cellcycle checkpoints.”

  • The paper relies on this without support.

    The catalytic domains of PIKK family members transfer phosphate exclusively to protein rather than lipid substrates.

    “Despite the sequence similarity to phosphoinositide kinases, the catalytic domains of the PIKKs appear to transfer phosphate exclusively to protein rather than lipid substrates.”

  • The paper relies on this without support.

    ATM-deficient cells display significant defects in the G1, S, and G2 checkpoints.

    “Before the cloning of the ATM gene, the dedicated efforts ATM/ATR kinases and checkpoint signaling of many laboratories documented that ATM-deficient cells displayed significant defects in the G 1 , S, and G 2 checkpoints.”

  • The paper relies on this without support.

    Rad1, Rad9, and Hus1 form a heterotrimeric complex in intact cells.

    “Rad1, Rad9, and Hus1 are also found as a heterotrimeric complex in intact cells, and it has been postulated that the Rad1-Rad9-Hus1 complex encircles DNA at or near sites of damage to form a checkpoint sliding clamp (CSC) (O'Connell et al. 2000), which could serve as a nucleus for the recruitment of the checkpoint signaling machinery to broken or abnormally structured DNA.”

  • The paper relies on this without support.

    Most or all forms of genotoxic stress rapidly increase p53 levels primarily by increasing p53 protein stability.

    “DNA damage induced by most, if not all, forms of genotoxic stress induces a rapid increase in the level of p53, a response that is mediated primarily through an increase in protein stability.”

  • The paper relies on this without support.

    Genotoxic stress induces posttranslational modifications that regulate p53 transcriptional activation.

    “In addition to triggering the accumulation of p53, genotoxic stress induces posttranslational modifications that regulate the transcriptional activating functions of this protein.”

  • The paper relies on this without support.

    p21 is a key transcriptional target of p53 for the G1 checkpoint.

    “With respect to the G 1 checkpoint, a key target for transcriptional activation by p53 is the cyclin-dependent kinase inhibitor, p21 (also termed WAF1 or CIP1).”

  • The paper relies on this without support.

    The p53-dependent increase in p21 suppresses cyclin E- and cyclin A-associated cdk2 activities, preventing G1-to-S progression.

    “The p53-dependent increase in p21 expression suppresses cyclin Eand cyclin A-associated cdk2 activities, and thereby prevents G 1 -to-S phase progression.”

  • The paper relies on this without support.

    Nonhomologous repair mechanisms are inherently less precise and increase the risk that inaccurately repaired DNA is carried into M phase.

    “Nonhomologous repair mechanisms also play very prominent roles in DNA dsb repair during all phases of the cell cycle; however, these mechanisms are inherently less precise, and therefore confer an increased risk that inaccurately repaired DNA will be carried forward into M phase.”

  • The paper relies on this without support.

    A main route by which tumor cells become genetically unstable is mutation that impairs or removes cell-cycle checkpoints.

    “A major mechanism whereby tumor cells acquire genetic instability is through the acquisition of mutations that weaken or eliminate cell-cycle checkpoints.”

  • The paper relies on this without support.

    Checkpoint control loss occurs especially often as cancer advances.

    “Loss of checkpoint controls is particularly prevalent in the later stages of cancer development, and it is these tumor cells that tend to be especially refractory to killing by conventional anticancer agents, many of which either damage DNA directly or interfere with DNA replication.”

  • The paper relies on this without support.

    Such checkpoint-deficient tumor cells are often hard to kill with standard anticancer drugs that damage DNA or block replication.

    “Loss of checkpoint controls is particularly prevalent in the later stages of cancer development, and it is these tumor cells that tend to be especially refractory to killing by conventional anticancer agents, many of which either damage DNA directly or interfere with DNA replication.”
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Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Residue 18 is identified as both serine and threonine

    Minor

    The text calls p53 residue 18 a serine, while the cited reference identifies the same residue as threonine.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 3

  1. Jung, 1997, ATM gene product phosphorylates I κ B-α., Cancer Res., 57, 24
  2. Kroutil L.C. Kunkel T.A. (1998) DNA replication errors involving strand misalignments. in Genetic instabilities and hereditary neurological diseases, eds Wells R.D. Warren S.T. (Academic Press, San Diego, CA), pp 699–716.
  3. Maquat L.E. (2000) Nonsense-mediated mRNA decay in human cells: A splicing-dependent means to downregulate the levels of mRNAs that prematurely terminate translation. in Translational control of gene expression, eds Sonenberg N. Hershey J.W.B. Mathews M.B. (Cold Spring Harbor Laboratory Press, Cold Spring Harbor, NY), pp 849–868.

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Authors
Abraham, R. T.
Affiliations
Duke University (US)
Corresponding author
Abraham, Robert T.
ORCID
Abraham, Robert T.
Venue
Genes & Development
Publisher
Cold Spring Harbor Laboratory
Published
2001-09-01
Volume
15
Issue
17
Pages
2177-2196
ISSN
  • 0890-9369 (ISSN-L)
  • 1549-5477
DOI
10.1101/gad.914401
OpenAlex
W2128252882
Semantic Scholar
4d2e287782bf5eb59858e4df82b3dea9790fc922
Cited by
1,966
References
151
Citations by year
2026: 13 · 2025: 20 · 2024: 23 · 2023: 42 · 2022: 39 · 2021: 53 · 2020: 45 · 2019: 59 · 2018: 50 · 2017: 66 · 2016: 57 · 2015: 65 · 2014: 65 · 2013: 93 · 2012: 91
Type
posted content
Language
en
Open access
Locations
  • Genes & Development (publishedVersion)
  • PubMed (publishedVersion)
Funders
National Cancer Institute (CA76193, R01CA076193)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
cell cycle checkpoints, ATM kinase, ATR kinase, DNA damage response, DNA replication errors, reactive oxygen species, UV-induced DNA damage, genome stability, cancer
MeSH terms
Animals, DNA, Fungal Proteins, Humans, Mitosis, Models, Biological, Signal Transduction, G1 Phase, G2 Phase, S Phase, Protein Serine-Threonine Kinases, Protein Structure, Tertiary, ATP-Binding Cassette Transporters, Cell Cycle Proteins, Saccharomyces cerevisiae Proteins, Ataxia Telangiectasia Mutated Proteins

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 2026-10-05.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-05.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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