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Cited by 69Cancer-related Molecular PathwaysDNA Repair MechanismsChromatin Remodeling and Cancer

Mdmx promotes genomic instability independent of p53 and Mdm2

Open access
Carrillo, A M, Bouska, A, Arrate, M P, Eischen, C M·2015·Oncogene
DOI 10.1038/onc.2014.27PMC PMC4160436
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Abstract

The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor. However, a p53-independent function of Mdmx that impacts genome stability has been described, but this function is not well understood. In the present study, we determined that of the 13 different cancer types evaluated, 6–90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53. We show elevated levels of Mdmx-inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability. Mdmx impaired early DNA damage-response signaling, such as phosphorylation of the serine/threonine-glutamine motif, mediated by the ATM kinase. Moreover, we identified Mdmx associated with Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and this association increased upon DNA damage and was detected at chromatin. Elevated Mdmx levels also increased cellular transformation in a p53-independent manner. Unexpectedly, all Mdmx-mediated phenotypes also occurred in cells lacking Mdm2 and were independent of the Mdm2-binding domain (RING) of Mdmx. Therefore, Mdmx-mediated inhibition of the DNA damage response resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and Mdm2. Our results reveal a novel p53- and Mdm2-independent oncogenic function of Mdmx that provides new insight into the many cancers that overexpress Mdmx.

AI snapshot

Written from the paper’s full text.

TL;DR

Mdmx overexpression promotes genomic instability and cellular transformation independently of p53 and Mdm2 by associating with Nbs1 and impairing ATM-mediated DNA damage signaling, delaying double-strand break repair. These effects map to Mdmx amino acids 1–345 and Nbs1 amino acids 396–512 and occur even in p53/Mdm2-null cells.

Key findings

  • Across 13 cancer types, 6–90% of tumors with elevated Mdmx also had p53 inactivation; ovarian serous cystadenocarcinoma and lung squamous cell carcinoma showed 77–90% co-occurrence, breast cancer 27%, and 10 of 13 cancer types had p53 alterations in at least 10% of Mdmx-elevated tumors.
  • In p53−/− MEFs, Mdmx overexpression caused a 4.9-fold increase in chromatid breaks and a 2.8-fold increase in chromosome breaks; only 42% of Mdmx-overexpressing cells repaired double-strand breaks within 90 minutes post-γIR versus 79% of controls.
  • Mdmx inhibited early DNA damage signaling, with an approximately 35% reduction in pS/T-Q foci within the initial 20 minutes after γIR, and delayed γH2AX foci resolution; these effects occurred without p53, Arf, or Mdm2 and with a Mdmx mutant lacking the RING domain (MxΔRING).
  • Mdmx co-immunoprecipitated with Nbs1, but not Mre11 or Rad50, via Mdmx aa 1–345 and Nbs1 aa 396–512; in p53−/−Mdm2−/− MEFs, Mdmx increased cells with chromatid/chromosome breaks 3-fold, chromosome fusions 5-fold, and soft agar colony formation.

Methods

  • Used p53−/−, Arf−/−, p53−/−Mdm2−/−, Atm−/−Arf−/− MEFs, 293T cells, and human retinal epithelial cells; overexpressed wild-type Mdmx, MxΔRING, or Mdm2 via retroviral/bicistronic vectors.
  • Assessed genome instability by metaphase chromosome analysis, DNA repair by neutral comet assay after 5 Gy γIR, DNA damage signaling by γH2AX and pS/T-Q immunofluorescence, protein interactions by co-immunoprecipitation, chromatin recruitment by fractionation, and transformation by soft agar colony formation.
  • TCGA data were accessed through cBioPortal in October 2013 for copy number, mutation, and mRNA expression; statistical significance used Fisher’s exact test, Student’s t-test, or 95% confidence intervals as appropriate.

Limitations

  • The paper does not state limitations.
  • Evident from the text: most mechanistic work relies on overexpression in murine embryonic fibroblasts and in vitro assays, with transformation measured by soft agar colony formation rather than in vivo tumorigenesis; TCGA analysis is cross-sectional and from 2013, so it cannot establish causality between Mdmx elevation and p53 inactivation.

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

Integrity signals

Registry

Crossref · 10.1038/onc.2014.27

Cites

55 of 55 references verified0 citation errors · 0 not checkable

Statistics

Nothing to recompute.

Claims the paper makes

0 of 96 cited sources checked · 0 supported · 0 flagged

  • Findingown data

    Elevated Mdmx increases cellular transformation in a p53-independent manner.

    “Elevated Mdmx levels also increased cellular transformation in a p53-independent manner.”
    Quote in the paperSubstantial claim
  • Findingown data

    Among thirteen cancer types evaluated, 6-90% of those with elevated Mdmx had concurrent inactivation (mutation or deletion) of p53.

    “In the present study, we determined that of the thirteen different cancer types evaluated, 6–90% of those that had elevated levels of Mdmx had concurrent inactivation (mutated or deleted) of p53.”
    Quote in the paperNot a substantial claim
  • Findingown data

    Elevated Mdmx induces chromosome and chromatid breaks independently of p53.

    “We show elevated levels of Mdmx inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability.”
    • Also stated in: § Elevated Mdmx increases genome instability independent of p53 · plain
      “Mdmx overexpression alone significantly increased the prevalence of cells with breaks (chromatid or chromosome; Figure 1).”
    Quote in the paperSubstantial claim
  • Findingown data

    Mdmx impairs early DNA damage response signaling, including phosphorylation of the serine/threonine-glutamine motif mediated by ATM.

    “Mdmx impaired early DNA damage response signaling, such as phosphorylation of the serine/threonine-glutamine motif, mediated by the ATM kinase.”
    Quote in the paperSubstantial claim
  • Findingown data

    Elevated Mdmx inhibits double-strand DNA break repair independently of p53.

    “We show elevated levels of Mdmx inhibited double-strand DNA break repair and induced chromosome and chromatid breaks independent of p53, leading to genome instability.”
    • Also stated in: § Mdmx inhibits double-strand DNA break repair independent of p53 and Mdm2 · plain
      “Therefore, Mdmx inhibited DNA double-strand break repair independent of p53.”
    Quote in the paperSubstantial claim
  • May combine two claims. 41
  • Classified as probably not a substantial claim. 24

  • May combine two claims.

    Findingown data

    All Mdmx-mediated phenotypes occur in cells lacking Mdm2 and are independent of the Mdm2-binding RING domain of Mdmx.

    “Unexpectedly, all Mdmx-mediated phenotypes also occurred in cells lacking Mdm2 and were independent of the Mdm2-binding domain (RING) of Mdmx.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mdmx associates with Nbs1 of the MRN complex, and this association increases upon DNA damage and is detected at chromatin.

    “Moreover, we identified Mdmx associated with Nbs1 of the Mre11-Rad50-Nbs1 (MRN) DNA repair complex, and this association increased upon DNA damage and was detected at chromatin.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    MxΔRING promotes chromatid and chromosome breaks and inhibits double-strand DNA break repair analogously to full-length Mdmx.

    “Surprisingly, the Mdmx mutant was also able to promote chromatid and chromosome breaks and inhibit double-strand DNA break repair analogous to full-length Mdmx (Figures 1A and 2B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ranking of γH2AX foci in individual cells from p53−/− and p53−/−Mdm2−/− MEFs revealed an overall reduction in foci at 5 minutes and an overall increase at 150 minutes following γIR in Mdmx and MxΔRING expressing MEFs.

    “Ranking of γH2AX foci in individual cells from a representative experiment of p53−/− and p53−/−Mdm2−/− MEFs revealed that there was an overall reduction in foci at 5 minutes and an overall increase in foci at 150 minutes following γIR in the Mdmx and the MxΔRING expressing MEFs (Figure 3B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both wild-type Mdmx and MxΔRING effectively delay double-strand DNA break repair in Arf−/− MEFs.

    “Both wild-type Mdmx and MxΔRING effectively delayed double-strand DNA break repair in cells lacking Arf (Figure 2C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Ranking of pS/T-Q foci in individual cells revealed an overall reduction at 10 minutes, a slightly lower or similar number at 60 minutes, and an overall increase at 240 minutes following γIR in Mdmx and MxΔRING expressing MEFs.

    “Ranking of pS/T-Q foci in individual cells from a representative experiment for each cell type revealed that there was an overall reduction in foci at 10 minutes, a slightly lower or similar number of foci at 60 minutes, and an overall increase in foci at 240 minutes following γIR in the Mdmx and the MxΔRING expressing MEFs (Figure 3F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Endogenous Nbs1 co-immunoprecipitates with endogenous Mdmx in both p53−/− and p53−/−Mdm2−/− MEFs, whereas Nbs1 is not detected in immunoprecipitations from control MEFs lacking Mdmx.

    “Specifically, endogenous Nbs1 co-immunoprecipitated with endogenous Mdmx in both p53−/− and p53−/−Mdm2−/− MEFs, whereas Nbs1 was not detected in immunoprecipitations from control MEFs lacking Mdmx (Figure 4B).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Nbs1 179-542, but not Nbs1 179-395, co-immunoprecipitates with MxΔRING.

    “Nbs1 179–542, but not Nbs1 179–395, co-immunoprecipitated with MxΔRING (Figure 4F).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Both full-length Nbs1 and Nbs1 1-592 co-immunoprecipitate with Mdmx, but Nbs1 513-754 does not.

    “Both full-length Nbs1 and Nbs1 1–592 co-immunoprecipitated with Mdmx, but Nbs1 513–754 did not (Figure 4E).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mdm2 is not required for Mdmx to exert its effect on pS/T-Q foci; MxΔRING in p53−/− MEFs and human retinal epithelial cells and wild-type Mdmx in p53−/−Mdm2−/− MEFs produced similar results.

    “Notably, Mdm2 was not required for Mdmx to exert this effect, as MxΔRING in p53−/− MEFs and human retinal epithelial cells and wild-type Mdmx in p53−/−Mdm2−/− MEFs produced similar results (Figures 3D and 3E; Supplementary Figure S1C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingcitation

    Mutant Mdmx effectively inhibits DNA break repair in human retinal epithelial cells that retain p53 and Arf and frequently overexpress MDMX when transformed, as in retinoblastoma.

    “Furthermore, this mutant form of Mdmx effectively inhibited DNA break repair in human retinal epithelial cells, which retain p53 and Arf and frequently overexpress MDMX when transformed, as in retinoblastoma.22”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [22] Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, Fuller C et al. Inactivation of the p53 pathway in retinoblastoma. Nature 2006; 444: 61–66. source

      Not checked in the free run.

  • May combine two claims.

    Findingown data

    Mdmx delays resolution of pS/T-Q and γH2AX foci, leading to more foci at later times after DNA damage and prolonging the response.

    “Finally, Mdmx delayed the resolution of pS/T-Q and γH2AX foci leading to a higher number of foci at later times after DNA damage, prolonging the DNA damage response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    Mdmx and Nbs1 interact, and this interaction increases after DNA double-strand breaks.

    “We detected Mdmx and Nbs1 interaction that increased following DNA double-strand breaks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Findingown data

    After DNA damage, Mdmx protein levels increase, localize to chromatin, and associate with Nbs1.

    “we observed increased levels of Mdmx protein localizing to chromatin and associating with Nbs1 following DNA damage.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Mdmx-mediated inhibition of the DNA damage response results in delayed DNA repair and increased genome instability and transformation independently of p53 and Mdm2.

    “Therefore, Mdmx-mediated inhibition of the DNA damage response resulted in delayed DNA repair and increased genome instability and transformation independent of p53 and Mdm2.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The MRN complex senses and processes double-strand DNA breaks and activates downstream DNA damage response proteins such as ATM.

    “The MRN complex is important in sensing and processing double-strand DNA breaks, as well as activating downstream DNA damage response proteins that mediate or signal for DNA repair, such as the DNA damage-induced kinase ATM.9–13”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [9] Bekker-Jensen S, Mailand N . Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair (Amst) 2010; 9: 1219–1228. source

      Not checked in the free run.

    • cites [10] Stracker TH, Petrini JH . The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 2011; 12: 90–103. source

      Not checked in the free run.

    • cites [11] Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y . Requirement of the MRN complex for ATM activation by DNA damage. Embo J 2003; 22: 5612–5621. source

      Not checked in the free run.

    • cites [12] Lee JH, Paull TT . ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 2005; 308: 551–554. source

      Not checked in the free run.

    • cites [13] Difilippantonio S, Celeste A, Fernandez-Capetillo O, Chen HT, Reina San Martin B, Van Laethem F et al. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat Cell Biol 2005; 7: 675–685. source

      Not checked in the free run.

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

    Premisecitation

    Mdmx is overexpressed in many human malignancies and, together with Mdm2, negatively regulates the p53 tumor suppressor.

    “The oncogene Mdmx is overexpressed in many human malignancies, and together with Mdm2, negatively regulates the p53 tumor suppressor.”
    Quote in the paperNot a substantial claim0 of 6 sources checked
    • cites [3] Wade M, Li YC, Wahl GM . MDM2 MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83–96. source

      Not checked in the free run.

    • cites [18] Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 2004; 24: 5835–5843. source

      Not checked in the free run.

    • cites [19] Ramos YF, Stad R, Attema J, Peltenburg LT, van der Eb AJ, Jochemsen AG . Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer Res 2001; 61: 1839–1842.

      Not checked in the free run.

    • cites [20] Leventaki V, Rodic V, Tripp SR, Bayerl MG, Perkins SL, Barnette P et al. TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases. Br J Haematol 2012; 158: 763–771. source

      Not checked in the free run.

    • cites [24] Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP et al. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2001; 2: 1029–1034. source

      Not checked in the free run.

    • cites [25] Marine JC, Dyer MA, Jochemsen AG . MDMX: from bench to bedside. J Cell Sci 2007; 120: 371–378. source

      Not checked in the free run.

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

    Premisecitation

    Mdm2 has p53-independent functions that affect genome stability and contribute to tumorigenesis.

    “studies have identified other functions of Mdm2 that impact genome stability that are independent of p53 and contribute to tumorigenesis.4–7”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [4] Lundgren K, Montes de Oca Luna R, McNeill YB, Emerick EP, Spencer B, Barfield CR et al. Targeted expression of MDM2 uncouples S phase from mitosis and inhibits mammary gland development independent of p53. Genes Dev 1997; 11: 714–725. source

      Not checked in the free run.

    • cites [5] Alt JR, Bouska A, Fernandez MR, Cerny RL, Xiao H, Eischen CM . Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair. J Biol Chem 2005; 280: 18771–18781. source

      Not checked in the free run.

    • cites [6] Bouska A, Lushnikova T, Plaza S, Eischen CM . Mdm2 promotes genetic instability and transformation independent of p53. Mol Cell Biol 2008; 28: 4862–4874. source

      Not checked in the free run.

    • cites [7] Jones SN, Hancock AR, Vogel H, Donehower LA, Bradley A . Overexpression of Mdm2 in mice reveals a p53-independent role for Mdm2 in tumorigenesis. Proc Natl Acad Sci USA 1998; 95: 15608–15612. source

      Not checked in the free run.

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

    Premisecitation

    Mdm2 is an E3 ubiquitin ligase and a negative regulator of p53 that is frequently overexpressed in human malignancies.

    “The E3 ubiquitin ligase Mdm2, a negative regulator of the p53 tumor suppressor, is frequently overexpressed in many human malignancies.1–3”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [1] Momand J, Jung D, Wilczynski S, Niland J . The MDM2 gene amplification database. Nucleic Acids Res 1998; 26: 3453–3459. source

      Not checked in the free run.

    • cites [2] Rayburn E, Zhang R, He J, Wang H . MDM2 and human malignancies: expression, clinical pathology, prognostic markers, and implications for chemotherapy. Curr Cancer Drug Targets 2005; 5: 27–41. source

      Not checked in the free run.

    • cites [3] Wade M, Li YC, Wahl GM . MDM2 MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83–96. source

      Not checked in the free run.

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

    Premisecitation

    Genome instability is a hallmark of cancer and a known contributor to tumorigenesis.

    “Genome instability is a hallmark of cancer and is a known contributor to tumorigenesis.14,15”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [14] Negrini S, Gorgoulis VG, Halazonetis TD . Genomic instability—an evolving hallmark of cancer. Nat Rev Mol Cell Biol 2010; 11: 220–228. source

      Not checked in the free run.

    • cites [15] Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674. source

      Not checked in the free run.

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

    Premisecitation

    ATM phosphorylates H2AX and hundreds of other proteins upon double-strand DNA breaks.

    “ATM is a DNA damage response kinase that phosphorylates H2AX and hundreds of other proteins upon double-strand DNA breaks.38”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [38] Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007; 316: 1160–1166. source

      Not checked in the free run.

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

    Premisecitation

    Altered DNA repair is a significant contributing factor to genomic instability.

    “altered DNA repair has been implicated as a significant contributing factor.10”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [10] Stracker TH, Petrini JH . The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 2011; 12: 90–103. source

      Not checked in the free run.

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

    Premisecitation

    Elevated MDMX mRNA is detected in 65% of retinoblastomas, and the same percentage of cutaneous melanomas overexpress MDMX protein.

    “Elevated levels of levels of MDMX mRNA are detected in 65% of retinoblastomas and the same percentage of cutaneous melanomas overexpress MDMX protein.21,22”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [21] Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 2012; 18: 1239–1247. source

      Not checked in the free run.

    • cites [22] Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, Fuller C et al. Inactivation of the p53 pathway in retinoblastoma. Nature 2006; 444: 61–66. source

      Not checked in the free run.

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

    Premisecitation

    MDMX is overexpressed or amplified in at least 15% of human cancers.

    “MDMX, also known as MDM4, is overexpressed or amplified in at least 15% of human cancers.3,18–20”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [3] Wade M, Li YC, Wahl GM . MDM2 MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83–96. source

      Not checked in the free run.

    • cites [18] Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 2004; 24: 5835–5843. source

      Not checked in the free run.

    • cites [19] Ramos YF, Stad R, Attema J, Peltenburg LT, van der Eb AJ, Jochemsen AG . Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer Res 2001; 61: 1839–1842.

      Not checked in the free run.

    • cites [20] Leventaki V, Rodic V, Tripp SR, Bayerl MG, Perkins SL, Barnette P et al. TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases. Br J Haematol 2012; 158: 763–771. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Homozygous Myc-tagged Mdmx transgene expression is embryonic lethal and cannot be rescued by p53 deletion, suggesting a p53-independent function of Mdmx in development.

    “Although Mdmx inhibits p53 function, homozygous Myc-tagged Mdmx transgene expression was embryonic lethal, and this could not be rescued with deletion of p53,29 suggesting a p53-independent function of Mdmx in development.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [29] De Clercq S, Gembarska A, Denecker G, Maetens M, Naessens M, Haigh K et al. Widespread overexpression of epitope-tagged Mdm4 does not accelerate tumor formation in vivo. Mol Cell Biol 2010; 30: 5394–5405. source

      Not checked in the free run.

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

    Premisecitation

    Patients with congenital mutations in DNA repair proteins such as NBS1 and ATM have increased chromosomal fragility and increased incidence of tumor formation.

    “This is evident in patients with congenital mutations in DNA repair proteins, such as NBS1 and ATM. Cells from these patients have increased chromosomal fragility, and the patients themselves have an increased incidence of tumor formation.10,16,17”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [10] Stracker TH, Petrini JH . The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 2011; 12: 90–103. source

      Not checked in the free run.

    • cites [16] Varon R, Vissinga C, Platzer M, Cerosaletti KM, Chrzanowska KH, Saar K et al. Nibrin, a novel DNA double-strand break repair protein, is mutated in Nijmegen breakage syndrome. Cell 1998; 93: 467–476. source

      Not checked in the free run.

    • cites [17] Carney JP, Maser RS, Olivares H, Davis EM, Le Beau M, Yates JR 3rd et al. The hMre11/hRad50 protein complex and Nijmegen breakage syndrome: linkage of double-strand break repair to the cellular DNA damage response. Cell 1998; 93: 477–486. source

      Not checked in the free run.

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

    Premisecitation

    Mdmx was initially described as an Mdm2 homologue with high conservation in the N-terminal p53 binding domain and the C-terminal RING domain.

    “Mdmx was initially described as an Mdm2 homologue with high conservation in the N-terminal p53 binding domain and the C-terminal RING domain;23”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [23] Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. Embo J 1996; 15: 5349–5357. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Increased levels of Mdmx inhibit an early DNA damage signaling response, leading to an extension of this response and a delay in resolution of DNA breaks.

    “Taken together, these data indicate increased levels of Mdmx inhibit an early DNA damage signaling response, leading to an extension of this response and a delay in the resolution of the DNA breaks.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Through their RING domains, Mdmx binds Mdm2 and enhances Mdm2's ability to regulate p53.

    “Additionally, it has been shown that through their RING domains, Mdmx binds Mdm2 and enhances the ability of Mdm2 to regulate p53.23,24,26–28”
    Quote in the paperNot a substantial claim0 of 5 sources checked
    • cites [23] Shvarts A, Steegenga WT, Riteco N, van Laar T, Dekker P, Bazuine M et al. MDMX: a novel p53-binding protein with some functional properties of MDM2. Embo J 1996; 15: 5349–5357. source

      Not checked in the free run.

    • cites [24] Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP et al. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2001; 2: 1029–1034. source

      Not checked in the free run.

    • cites [26] Tanimura S, Ohtsuka S, Mitsui K, Shirouzu K, Yoshimura A, Ohtsubo M . MDM2 interacts with MDMX through their RING finger domains. FEBS Lett 1999; 447: 5–9. source

      Not checked in the free run.

    • cites [27] Sharp DA, Kratowicz SA, Sank MJ, George DL . Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem 1999; 274: 38189–38196. source

      Not checked in the free run.

    • cites [28] Pei D, Zhang Y, Zheng J . Regulation of p53: a collaboration between Mdm2 and Mdmx. Oncotarget 2012; 3: 228–235. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mdmx negatively regulates p53 by inhibiting p53 transcriptional activity rather than by promoting p53 degradation through ubiquitination.

    “While Mdmx negatively regulates p53, it does so through inhibiting p53 transcriptional activity rather than promoting p53 degradation through ubiquitination, as is the case for Mdm2.24,25”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [24] Stad R, Little NA, Xirodimas DP, Frenk R, van der Eb AJ, Lane DP et al. Mdmx stabilizes p53 and Mdm2 via two distinct mechanisms. EMBO Rep 2001; 2: 1029–1034. source

      Not checked in the free run.

    • cites [25] Marine JC, Dyer MA, Jochemsen AG . MDMX: from bench to bedside. J Cell Sci 2007; 120: 371–378. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Human tumors with MDMX overexpression may also have inactivated p53, indicating a potential oncogenic benefit from Mdmx overexpression in addition to p53 inhibition.

    “Moreover, human tumors with MDMX overexpression may also have inactivated p53,3,19,30,31 which indicates a potential oncogenic benefit to the cancer cells from Mdmx overexpression in addition to its inhibition of p53.”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [3] Wade M, Li YC, Wahl GM . MDM2 MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83–96. source

      Not checked in the free run.

    • cites [19] Ramos YF, Stad R, Attema J, Peltenburg LT, van der Eb AJ, Jochemsen AG . Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer Res 2001; 61: 1839–1842.

      Not checked in the free run.

    • cites [30] Giglio S, Mancini F, Gentiletti F, Sparaco G, Felicioni L, Barassi F et al. Identification of an aberrantly spliced form of HDMX in human tumors: a new mechanism for HDM2 stabilization. Cancer Res 2005; 65: 9687–9694. source

      Not checked in the free run.

    • cites [31] Lam S, Lodder K, Teunisse AF, Rabelink MJ, Schutte M, Jochemsen AG . Role of Mdm4 in drug sensitivity of breast cancer cells. Oncogene 2010; 29: 2415–2426. source

      Not checked in the free run.

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

    Premisecitation

    Mdmx regulates p53.

    “While it is clear Mdmx regulates p53,25,43”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Marine JC, Dyer MA, Jochemsen AG . MDMX: from bench to bedside. J Cell Sci 2007; 120: 371–378. source

      Not checked in the free run.

    • cites [43] Wade M, Wang YV, Wahl GM . The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 2010; 20: 299–309. source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Premisecitation

    Genome instability is linked to tumorigenesis.

    “genome instability is linked to tumorigenesis.15”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [15] Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Mdmx overexpression promotes transformation independently of p53 regulation and does not require Mdm2.

    “Therefore, Mdmx overexpression promoted transformation, and this was independent of its regulation of p53 and did not require Mdm2.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Mdmx interacts with Nbs1 and not Mre11 or Rad50.

    “These data indicate Mdmx interacts with Nbs1 and not Mre11 or Rad50.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The phosphorylation site ATM prefers is a serine or threonine followed by a glutamine (S/T-Q).

    “The phosphorylation site ATM prefers is a serine or threonine followed by a glutamine (S/T-Q).38,39”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [38] Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007; 316: 1160–1166. source

      Not checked in the free run.

    • cites [39] Kim ST, Lim DS, Canman CE, Kastan MB . Substrate specificities and identification of putative substrates of ATM kinase family members. J Biol Chem 1999; 274: 37538–37543. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    The region of Mdmx that associates with the MRN complex lies within amino acids 1-345, the same region that induced genome instability and inhibited DNA break repair and the DNA damage response.

    “Thus, the region of Mdmx that associates with the MRN complex lies within amino acids 1–345, the same region that induced genome instability (Figure 1A) and inhibited DNA break repair (Figure 2; Supplementary Figure S1A) and the DNA damage response (Figure 3; Supplementary Figures S1B and S1C).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The RING domain of Mdmx is dispensable for its interaction with Nbs1 of the MRN complex, and a specific region of Nbs1 is required for this association.

    “Collectively, the data show the RING domain of Mdmx is dispensable for its interaction with Nbs1 of the MRN complex, and a specific region of Nbs1 is required for this association.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Elevated levels of Mdmx severely blunt the early DNA damage response signal mediated by ATM, causing the response to be prolonged and resulting in the delay in DNA break repair.

    “These data illustrate that elevated levels of Mdmx severely blunt the early DNA damage response signal mediated by ATM causing the response to be prolonged, resulting in the delay in DNA break repair observed (Figure 2).”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Elevated Mdmx levels are observed in many tumors and during tumorigenesis.

    “elevated Mdmx levels are observed in many tumors.3,18–22”
    • Also stated in: § Discussion · plain
      “When Mdmx levels were elevated, which occurs during tumorigenesis”
    Quote in the paperSubstantial claim0 of 6 sources checked
    • cites [3] Wade M, Li YC, Wahl GM . MDM2 MDMX and p53 in oncogenesis and cancer therapy. Nat Rev Cancer 2013; 13: 83–96. source

      Not checked in the free run.

    • cites [18] Danovi D, Meulmeester E, Pasini D, Migliorini D, Capra M, Frenk R et al. Amplification of Mdmx (or Mdm4) directly contributes to tumor formation by inhibiting p53 tumor suppressor activity. Mol Cell Biol 2004; 24: 5835–5843. source

      Not checked in the free run.

    • cites [19] Ramos YF, Stad R, Attema J, Peltenburg LT, van der Eb AJ, Jochemsen AG . Aberrant expression of HDMX proteins in tumor cells correlates with wild-type p53. Cancer Res 2001; 61: 1839–1842.

      Not checked in the free run.

    • cites [20] Leventaki V, Rodic V, Tripp SR, Bayerl MG, Perkins SL, Barnette P et al. TP53 pathway analysis in paediatric Burkitt lymphoma reveals increased MDM4 expression as the only TP53 pathway abnormality detected in a subset of cases. Br J Haematol 2012; 158: 763–771. source

      Not checked in the free run.

    • cites [21] Gembarska A, Luciani F, Fedele C, Russell EA, Dewaele M, Villar S et al. MDM4 is a key therapeutic target in cutaneous melanoma. Nat Med 2012; 18: 1239–1247. source

      Not checked in the free run.

    • cites [22] Laurie NA, Donovan SL, Shih CS, Zhang J, Mills N, Fuller C et al. Inactivation of the p53 pathway in retinoblastoma. Nature 2006; 444: 61–66. source

      Not checked in the free run.

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

    Study design and conductnone given

    At least three independent experiments were performed for all analyses.

    “A minimum of three independent experiments were performed for all analyses.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Transgenic mice overexpressing Mdmx have an increased incidence of malignancies.

    “Recently, it was reported that transgenic mice overexpressing Mdmx had an increased incidence of malignancies.52”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Xiong S, Pant V, Suh YA, Van Pelt CS, Wang Y, Valentin-Vega YA et al. Spontaneous tumorigenesis in mice overexpressing the p53-negative regulator Mdm4. Cancer Res 2010; 70: 7148–7154. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mdmx−/−p53−/− MEFs have multipolar spindle formation and altered chromosome number.

    “Specifically, Mdmx−/−p53−/− MEFs had multipolar spindle formation and altered chromosome number.32,33”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [32] Matijasevic Z, Steinman HA, Hoover K, Jones SN . MdmX promotes bipolar mitosis to suppress transformation and tumorigenesis in p53-deficient cells and mice. Mol Cell Biol 2008; 28: 1265–1273. source

      Not checked in the free run.

    • cites [33] Matijasevic Z, Krzywicka-Racka A, Sluder G, Jones SN . MdmX regulates transformation and chromosomal stability in p53-deficient cells. Cell Cycle 2008; 7: 2967–2973. source

      Not checked in the free run.

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

    Premisecitation

    Phosphorylation of H2AX and S/T-Q sites occurs rapidly after DNA breaks.

    “Phosphorylation of H2AX and S/T-Q sites, both of which are targets of ATM, occurs rapidly after DNA breaks.9,37,38”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [9] Bekker-Jensen S, Mailand N . Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair (Amst) 2010; 9: 1219–1228. source

      Not checked in the free run.

    • cites [37] Rogakou EP, Pilch DR, Orr AH, Ivanova VS, Bonner WM . DNA double-stranded breaks induce histone H2AX phosphorylation on serine 139. J Biol Chem 1998; 273: 5858–5868. source

      Not checked in the free run.

    • cites [38] Matsuoka S, Ballif BA, Smogorzewska A, McDonald ER 3rd, Hurov KE, Luo J et al. ATM and ATR substrate analysis reveals extensive protein networks responsive to DNA damage. Science 2007; 316: 1160–1166. source

      Not checked in the free run.

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

    Premisecitation

    Genome instability can precede tumor formation, characterizes malignant cells, and is associated with defective DNA damage responses.

    “Genome instability can be a precursor to tumor formation, is a hallmark of malignant cells, and is connected with impairments in the DNA damage response.10,15”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [10] Stracker TH, Petrini JH . The MRE11 complex: starting from the ends. Nat Rev Mol Cell Biol 2011; 12: 90–103. source

      Not checked in the free run.

    • cites [15] Hanahan D, Weinberg RA . Hallmarks of cancer: the next generation. Cell 2011; 144: 646–674. source

      Not checked in the free run.

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

    Premisecitation

    Mdmx can regulate p53 independently of Mdm2.

    “it is known that Mdmx can regulate p53 independent of Mdm2.25,43”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [25] Marine JC, Dyer MA, Jochemsen AG . MDMX: from bench to bedside. J Cell Sci 2007; 120: 371–378. source

      Not checked in the free run.

    • cites [43] Wade M, Wang YV, Wahl GM . The p53 orchestra: Mdm2 and Mdmx set the tone. Trends Cell Biol 2010; 20: 299–309. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Mdmx inhibits phosphorylation of ATM targets, causing delayed DNA repair and increased chromosome and chromatid breaks.

    “Our results indicate Mdmx inhibits phosphorylation of ATM targets resulting in a delay in DNA repair and an increase in chromosome and chromatid breaks.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Either gain or loss of Mdmx negatively impacts genome integrity.

    “Thus, the data indicate that either gain or loss of Mdmx negatively impacts genome integrity”
    Quote in the paperSubstantial claim

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

    Premisecitation

    The RING domain of Mdmx is required for binding to Mdm2 through its RING domain.

    “The RING domain of Mdmx is required to bind to Mdm2 through its RING domain.26,27”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [26] Tanimura S, Ohtsuka S, Mitsui K, Shirouzu K, Yoshimura A, Ohtsubo M . MDM2 interacts with MDMX through their RING finger domains. FEBS Lett 1999; 447: 5–9. source

      Not checked in the free run.

    • cites [27] Sharp DA, Kratowicz SA, Sank MJ, George DL . Stabilization of the MDM2 oncoprotein by interaction with the structurally related MDMX protein. J Biol Chem 1999; 274: 38189–38196. source

      Not checked in the free run.

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

    Study design and conductown data

    In vitro transformation assays included at least two independent experiments with three replicates each.

    “At least two independent experiments consisting of three replicates each were performed.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Mice expressing Mdmx lacking or with mutant RING domain die in utero, and p53 deletion rescues this phenotype.

    “Mice engineered to express Mdmx lacking its RING domain or containing a mutant RING domain die in utero, and this phenotype was rescued with deletion of p53.50,51”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [50] Pant V, Xiong S, Iwakuma T, Quintas-Cardama A, Lozano G . Heterodimerization of Mdm2 and Mdm4 is critical for regulating p53 activity during embryogenesis but dispensable for p53 and Mdm2 stability. Proc Natl Acad Sci USA 2011; 108: 11995–12000. source

      Not checked in the free run.

    • cites [51] Huang L, Yan Z, Liao X, Li Y, Yang J, Wang ZG et al. The p53 inhibitors MDM2/MDMX complex is required for control of p53 activity in vivo. Proc Natl Acad Sci USA 2011; 108: 12001–12006. source

      Not checked in the free run.

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

    Study design and conductown data

    At least two independent experiments were performed and results pooled for metaphase analysis.

    “A minimum of two independent experiments were performed and the results pooled.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Full activation of ATM after DNA double-strand breaks requires Nbs1 of the MRN complex.

    “Full activation of ATM following DNA double-strand breaks requires Nbs1 of the MRN complex.9,11–13”
    Quote in the paperNot a substantial claim0 of 4 sources checked
    • cites [9] Bekker-Jensen S, Mailand N . Assembly and function of DNA double-strand break repair foci in mammalian cells. DNA Repair (Amst) 2010; 9: 1219–1228. source

      Not checked in the free run.

    • cites [11] Uziel T, Lerenthal Y, Moyal L, Andegeko Y, Mittelman L, Shiloh Y . Requirement of the MRN complex for ATM activation by DNA damage. Embo J 2003; 22: 5612–5621. source

      Not checked in the free run.

    • cites [12] Lee JH, Paull TT . ATM activation by DNA double-strand breaks through the Mre11-Rad50-Nbs1 complex. Science 2005; 308: 551–554. source

      Not checked in the free run.

    • cites [13] Difilippantonio S, Celeste A, Fernandez-Capetillo O, Chen HT, Reina San Martin B, Van Laethem F et al. Role of Nbs1 in the activation of the Atm kinase revealed in humanized mouse models. Nat Cell Biol 2005; 7: 675–685. source

      Not checked in the free run.

  • May combine two claims.

    Interpretationown data

    Elevated Mdmx causes a significant increase in genome instability and transformation attributed to inhibition of the DNA damage response.

    “When Mdmx levels were elevated, which occurs during tumorigenesis, we observed a significant increase in genome instability and transformation that are attributed to an inhibition in the DNA damage response.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    Regulation of the DNA break repair response by Mdmx and Mdm2 is a conserved function of this protein family, similar to their regulation of p53, and is present in multiple cell types.

    “Our data also reveal the regulation of the DNA break repair response by Mdmx and Mdm2 is a conserved function of this family of proteins, akin to their regulation of p53, and is present in multiple cell types.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationown data

    The effects of Mdmx on genome instability and transformation are independent of both p53 and Mdm2.

    “These effects of Mdmx were independent of both p53 and Mdm2.”
    Quote in the paperSubstantial claim
56 of 56

  • The paper relies on this without support.

    Experimental overexpression of Mdmx in MEFs and cell lines mimics the elevated Mdmx levels found in human cancers.

    “To mimic the cancer situation, we overexpressed Mdmx in p53−/− MEFs with a bicistronic retrovirus encoding HA-tagged Mdmx and YFP or as a control, YFP alone.”

  • The paper relies on this without support.

    Findings in murine embryonic fibroblasts and human cell lines are representative of human tumors that overexpress Mdmx.

    “Our results reveal a novel p53- and Mdm2-independent oncogenic function of Mdmx that provides new insight into the many cancers that overexpress Mdmx.”

  • The paper relies on this without support.

    The p53-independent functions of Mdmx had not been identified before this study.

    “Yet, identification of the p53-independent functions of Mdmx remained elusive.”

  • The paper relies on this without support.

    Transformation in the in vitro assays indicates tumorigenic potential in vivo.

    “Therefore, Mdmx overexpression promoted transformation”
    “Our data demonstrate Mdmx overexpression was sufficient to induce transformation of p53-null cells.”
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?

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.

  • H2AX phosphorylation is placed after repair rather than after damage

    Minor

    The Results say H2AX is rapidly phosphorylated following DNA break repair, but the Discussion says phosphorylation occurs rapidly after DNA breaks. These descriptions put the initial phosphorylation on opposite sides of repair.

1 of 1

Cites

1 retracted

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Authors
Carrillo, A. M., Bouska, A., Arrate, M. P., & Eischen, C. M.
Affiliations
  • Vanderbilt University Medical Center (US)
  • University of Nebraska Medical Center (US)
Corresponding author
Eischen, C M
ORCID
Venue
Oncogene
Publisher
Springer Science and Business Media LLC
Published
2014-03-10
Volume
34
Issue
7
Pages
846-856
ISSN
  • 0950-9232 (ISSN-L)
  • 1476-5594
DOI
10.1038/onc.2014.27
PMC
PMC4160436
OpenAlex
W2034333242
Semantic Scholar
3aaad6bd6f4bbe17a476beb40fbc380f9f04ae79
Cited by
69
References
55
Citations by year
2026: 1 · 2025: 7 · 2024: 7 · 2023: 4 · 2022: 2 · 2021: 6 · 2020: 6 · 2019: 6 · 2018: 3 · 2017: 8 · 2016: 10 · 2015: 6 · 2014: 3
FWCI
4.35
Type
journal article
Language
en
Open access
Licence
Locations
  • Oncogene (publishedVersion)
  • PubMed (publishedVersion)
  • PubMed Central (acceptedVersion)
Funders
National Cancer Institute (R01CA117935, R01CA160432, F31CA150546, T32CA009582, P30CA068485)
Topics
  • Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › DNA Repair Mechanisms
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
Keywords
MDMX, genomic instability, p53-independent function, MDM2, DNA double-strand break repair, DNA damage response, ATM kinase, MRN complex, NBS1, chromosome breakage, chromatid breaks, cell transformation, p53 inactivation
MeSH terms
MRE11 Homologue Protein, Animals, DNA Damage, DNA Repair, DNA-Binding Proteins, Humans, Neoplasms, Nuclear Proteins, Proto-Oncogene Proteins, Signal Transduction, Tumor Suppressor Protein p53, Acid Anhydride Hydrolases, Mice, Knockout, ATP-Binding Cassette Transporters, Cell Cycle Proteins, Genomic Instability, DNA Repair Enzymes, Mice, Proto-Oncogene Proteins c-mdm2

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 2026-10-08.

Classified by jev-1.13-20260917 (gold-guideline-v0.2) on 2026-10-08.

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