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Cited by 9Cancer-related Molecular PathwaysDNA Repair MechanismsHeat shock proteins research

Integration of DNA damage and repair with murine double-minute 2 (Mdm2) in tumorigenesis

Open access
Lehman, Jason, Mayo, Lindsey·2012·International Journal of Molecular Sciences
DOI 10.3390/ijms131216373PMC PMC3546695
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Abstract

The alteration of tumorigenic pathways leading to cancer is a degenerative disease process typically involving inactivation of tumor suppressor proteins and hyperactivation of oncogenes. One such oncogenic protein product is the murine double-minute 2, or Mdm2. While, Mdm2 has been primarily associated as the negative regulator of the p53 tumor suppressor protein there are many p53-independent roles demonstrated for this oncogene. DNA damage and chemotherapeutic agents are known to activate Mdm2 and DNA repair pathways. There are five primary DNA repair pathways involved in the maintenance of genomic integrity: Nucleotide excision repair (NER), Base excision repair (BER), Mismatch repair (MMR), Non-homologous end joining (NHEJ) and homologous recombination (HR). In this review, we will briefly describe these pathways and also delineate the functional interaction of Mdm2 with multiple DNA repair proteins. We will illustrate the importance of these interactions with Mdm2 and discuss how this is important for tumor progression, cellular proliferation in cancer.

AI snapshot

Written from the paper’s full text.

TL;DR

This review integrates the oncoprotein Mdm2 with five human DNA repair pathways—BER, HR, MMR, NER, and NHEJ—emphasizing p53-independent roles. It argues that Mdm2 can regulate DNA repair proteins through E3 ubiquitin ligase activity and other interactions, thereby promoting genomic instability and tumorigenesis.

Key findings

  • Mdm2 functions as an E3 ubiquitin ligase toward DNA repair proteins. In BER, Mdm2 led to Ape1 monoubiquitination, while the RING-finger Mdm2 mutant C464S did not; Ape1 ubiquitination was also acknowledged to be controlled by additional ligases.
  • In HR, Mdm2 binds Nbs1 within the MRN complex at DNA damage sites. Mdm2 overexpression inhibited Nbs1-directed double-strand break repair and led to elevated chromosome/chromatid breaks in a p53-null background, promoting p53-independent cellular transformation.
  • In NER, Mdm2 associates with DNA polymerase eta and targets it for polyubiquitination and proteasomal degradation after UV radiation. DDB2 silencing plus Mdm2 inhibited apoptosis with UV, cisplatin, and doxorubicin in HeLa cells, an effect reversed by silencing Mdm2.
  • In NHEJ, Mdm2 ubiquitinates Ku70 and decreases its levels when overexpressed or in mdm2/p53−/− MEFs, but not with the C464S mutant. DNA-PK phosphorylation of Mdm2 at Ser17 is also described as negating Mdm2–p53 binding. The MMR connection remains potential and not mechanistically substantiated.

Methods

  • Narrative literature review describing five primary human DNA repair pathways—BER, HR, MMR, NER, and NHEJ—and their reported functional interactions with Mdm2.
  • No primary experimental data, systematic search strategy, or meta-analysis is described; the paper synthesizes cited studies, including cell-line and MEF experiments, and summarizes key proteins in Tables 1 and 2.
  • Main analysis is conceptual integration of published findings on Mdm2-mediated ubiquitination, protein–protein interactions, and DNA repair regulation.

Limitations

  • The paper states that the connection between Mdm2 and key DNA repair proteins has been understudied, that a role for Mdm2 in MMR has yet to be described mechanistically, and that the contribution of Mdm2 splice variants to DNA repair is unknown.
  • The paper also notes that small-molecule development targeting Mdm2 must consider isoforms lacking the domains these molecules bind.
  • Evident from the text: many interactions are based on cited studies using overexpression or non-endogenous conditions—for example, Mdm2 and Ape1 interacted under overexpression but not as endogenous proteins—and several proposed links, such as physical complexes between DDB2 and Mdm2 or Mdm2 regulation of XPC, remain uninvestigated.

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

Integrity signals

Registry

Crossref · 10.3390/ijms131216373

Cites

Statistics

Nothing to recompute.

Claims the paper makes

0 of 61 cited sources checked · 0 supported · 0 flagged

  • Premisecitation

    Mdm2 and Nbs1 co-localize at sites of DNA damage after ionizing radiation induces double-strand breaks.

    “Further, Mdm2 and Nbs1 were found to co-localize together at sites of DNA damage after cells were treated with ionizing radiation to induce double-strand breaks [31].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [31] Alt, 2005, Mdm2 binds to Nbs1 at sites of DNA damage and regulates double strand break repair, J. Biol. Chem source

      Not checked in the free run.

  • Premisecitation

    Mdm2 overexpression leads to Mdm2-directed cellular transformation that is not dependent on p53.

    “This also led to Mdm2-directed cellular transformation not dependent on p53.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Bouska, 2008, Mdm2 promotes genetic instability and transformation independent of p53, Mol. Cell Biol source

      Not checked in the free run.

  • Premisecitation

    UV damage induces CUL4/DDB1 and PCNA, leading to Mdm2 proteolysis.

    “Data revealed UV damage induced CUL4/DDB1 and PCNA leading to Mdm2 proteolysis.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Banks, 2006, L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes, Cell Cycle source

      Not checked in the free run.

  • Premisecitation

    Mutation of a binding region critical for Mdm2 interaction leads to increased double-strand break repair rates.

    “Mutation of a binding region critical for interaction with Mdm2 led to increased DSB repair rates.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Bouska, 2008, Mdm2 promotes genetic instability and transformation independent of p53, Mol. Cell Biol source

      Not checked in the free run.

  • Premisecitation

    Mdm2 functions as an E3 ubiquitin ligase that conjugates ubiquitin to proteins including p53, signaling their destruction by the 26S proteasome to keep cellular p53 levels low.

    “Mdm2 typically functions as an E3 ubiquitin ligase and conjugates ubiquitin to several proteins including, the tumor suppressor p53. This ultimately signals for destruction by the 26S proteasome to keep cellular p53 levels low [1,2].”
    Quote in the paperSubstantial claim0 of 2 sources checked
    • cites [1] Brooks, 2011, p53 regulation by ubiquitin, FEBS Lett source

      Not checked in the free run.

    • cites [2] Kulikov, 2010, Mdm2 facilitates association of p53 with the proteasome, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

  • May combine two claims. 15
  • Classified as probably not a substantial claim. 19

  • May combine two claims.

    Premisecitation

    Ape1 ubiquitination at specific sites is at least partially dependent on Mdm2-mediated E3 ubiquitin ligase activity, but Ape1 ubiquitination is also controlled by additional ligases.

    “These sites were at least partially dependent on Mdm2-mediated E3 ubiquitin ligase activity, but the authors acknowledged that Ape1 ubiquitination is controlled by additional ligases.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [17] Busso, 2011, Ubiquitination of human AP-endonuclease 1 (APE1) enhanced by T233E substitution and by CDK5, Nucl. Acids Res source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The ARF/XPC data do not exclude an Mdm2-specific role in nucleotide excision repair, because Mdm2 has many p53-independent functions and the experiments were carried out in MEFs.

    “While they ruled out a p53-dependent ARF role, this data does not exclude an Mdm2-specific role, as Mdm2 is known to have many p53-independent functions and experiments were carried out in MEFs.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mdm2 and Ape1 interact under conditions of overexpression, but not as endogenous proteins.

    “Mdm2 and Ape1 were demonstrated to interact together under conditions of overexpression, yet not endogenous proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Busso, 2009, Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    The fact that Mdm2 inhibits double-strand break repair and interacts with Nbs1 supports its role in oncogenesis.

    “The fact that Mdm2 inhibits DSB repair and interacts with Nbs1 supports its role in oncogenesis.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Interpretationreasoning

    Regulation of Ape1 by Mdm2 exhibits a typical ubiquitin ligase mechanism that could become deregulated during cancer development.

    “Thus, it appears that regulation of the BER protein, Ape1 by Mdm2 exhibits a typical ubiquitin ligase mechanism, which could become deregulated during various steps leading to establishment of a cancer cell.”
    Quote in the paperSubstantial claim

  • May combine two claims.

    Premisecitation

    Mdm2 overexpression inhibits Nbs1-directed repair of double-strand breaks, leading to elevated chromosome/chromatid breaks.

    “Mdm2 overexpression led to an inhibition of Nbs1 directed repair of double strand breaks leading to elevated chromosome/chromatid breaks [32].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [32] Bouska, 2008, Mdm2 promotes genetic instability and transformation independent of p53, Mol. Cell Biol source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Ape1 is polyubiquitinated in HCT116 cells after H2O2 treatment, and purified Ape1 mixed with HeLa cell extracts forms a distinct monoubiquitination pattern.

    “Ape1 was found to be polyubiquitinated in a human cancer cell line, HCT116, after H2O2 treatment and purified Ape1 protein mixed with HeLa cell extracts formed a distinct monoubiquitination pattern [16].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [16] Busso, 2009, Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mdm2 leads to Ape1 monoubiquitination, whereas the RING-finger Mdm2 mutant C464S does not.

    “Examination of the E3 ligase Mdm2 showed that Mdm2 led to Ape1 monoubiquitination, while the RING-finger Mdm2 mutant (C464S) did not.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [16] Busso, 2009, Ubiquitination of mammalian AP endonuclease (APE1) regulated by the p53-MDM2 signaling pathway, Oncogene source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    The L2DTL/PCNA/CUL4/DDB1 complex regulates p53 polyubiquitination through Mdm2, and individual components interact with both proteins.

    “This multimeric protein complex regulated p53 polyubiquitination through Mdm2 and individual components were found to interact with both proteins.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [40] Banks, 2006, L2DTL/CDT2 and PCNA interact with p53 and regulate p53 polyubiquitination and protein stability through MDM2 and CUL4A/DDB1 complexes, Cell Cycle source

      Not checked in the free run.

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

    Premisecitation

    NHEJ repairs breaks induced by ionizing radiation, oxidative free radicals, misappropriate enzymatic action at sensitive sites, inhibition of topoisomerases, and other mechanical stresses.

    “DNA double-strand break repair or non-homologous end joining (NHEJ) repairs breaks induced by ionizing radiation (IR), oxidative free radicals, misappropriate enzymatic action at sensitive sites, inhibition of topoisomerases, and other mechanical stresses [54].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [54] Lieber, 2010, The mechanism of double-strand DNA break repair by the nonhomologous DNA end-joining pathway, Annu. Rev. Biochem source

      Not checked in the free run.

  • Classified as probably not a substantial claim.

    Interpretationnone given

    Multiple DNA repair pathways regulate the fidelity of duplex DNA and counteract specific subsets of lesions that can potentially alter genomic integrity.

    “Multiple DNA repair pathways regulate the fidelity of duplex DNA and are able to counteract specific subsets of lesions that can potentially alter genomic integrity.”
    Quote in the paperSubstantial claim

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

    Premisecitation

    Artemis nuclease is responsible for end processing.

    “The Artemis nuclease is responsible for end processing since blunt DNA ends are not always generated, especially after IR.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] Ma, 2002, Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination, Cell source

      Not checked in the free run.

    • cites [63] Pannicke, 2004, Functional and biochemical dissection of the structure-specific nuclease ARTEMIS, EMBO J source

      Not checked in the free run.

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

    Premisecitation

    DNA ligase IV completes the final steps of NHEJ to ligate DNA ends together while being held with XLF/XRCC4 and Ku/XRCC4 complexes.

    “DNA ligase IV completes the final steps of NHEJ to ligate DNA ends together while being held with XLF/XRCC4 and Ku/XRCC4 complexes [68,69].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [68] Ahnesorg, 2006, XLF interacts with the XRCC4-DNA ligase IV complex to promote DNA nonhomologous end-joining, Cell source

      Not checked in the free run.

    • cites [69] Callebaut, 2006, Cernunnos interacts with the XRCC4 x DNA-ligase IV complex and is homologous to the yeast nonhomologous end-joining factor Nej1, J. Biol. Chem source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mdm2 ubiquitinates Ku70 and decreases its levels in cells when Mdm2 is overexpressed or examined in mdm2/p53−/− MEFs, but not the RING-finger mutant C464S.

    “Mdm2 was determined to ubiquitinate Ku70 and decrease its levels in cells when Mdm2 is overexpressed or examined in mdm2/p53−/− MEFs, yet not the RING-finger mutant C464S [73].”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [73] Gama, 2009, Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization, Cell Death Differ source

      Not checked in the free run.

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

    Premisecitation

    DNA-PK phosphorylates and activates downstream effectors.

    “DNA-PK is believed to phosphorylate and activate downstream effectors [61].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [61] Ma, 2005, The DNA-dependent protein kinase catalytic subunit phosphorylation sites in human Artemis, J. Biol. Chem source

      Not checked in the free run.

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

    Premisecitation

    XLF/Cernunnos joins with XRCC4 to align DNA termini for more efficient end-joining.

    “The XRCC4 Like Factor (XLF/Cernunnos) functions biochemically to join with the XRCC4 protein to align DNA termini for more efficient end-joining [66,67].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [66] Hammel, 2010, XLF regulates filament architecture of the XRCC4.ligase IV complex, Structure source

      Not checked in the free run.

    • cites [67] Hammel, 2011, XRCC4 protein interactions with XRCC4-like factor (XLF) create an extended grooved scaffold for DNA ligation and double strand break repair, J. Biol. Chem source

      Not checked in the free run.

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

    Premisecitation

    The Ku70/Ku80 heterodimer is the first protein to bind to the end of a double-strand break.

    “The very first protein to bind to the end of the double-strand break is the Ku70/Ku80 heterodimer.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Andrews, 2006, Kinetic analysis of the Ku-DNA binding activity reveals a redox-dependent alteration in protein structure that stimulates dissociation of the Ku-DNA complex, J. Biol. Chem source

      Not checked in the free run.

    • cites [58] Lehman, 2008, DNA-dependent conformational changes in the Ku heterodimer, Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Interpretationreasoning

    Multiple nucleotide excision repair proteins are able to interact with Mdm2 and are subject to posttranslational modification by this E3 ubiquitin ligase.

    “Thus, there are multiple nucleotide excision repair proteins, which are able to interact with Mdm2 and are subject to posttranslational modification by this E3 ubiquitin ligase.”
    Quote in the paperNot a substantial claim

  • May combine two claims.

    Premisecitation

    Akt phosphorylates Mdm2 on S166/S186 and allows Mdm2 to move from the cytoplasm to nuclear compartment.

    “Akt has been shown to phosphorylate Mdm2 on S166/S186 and allow Mdm2 to move from the cytoplasm to nuclear compartment [74].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [74] Mayo, 2001, A phosphatidylinositol 3-kinase/Akt pathway promotes translocation of Mdm2 from the cytoplasm to the nucleus, Proc. Natl. Acad. Sci. USA source

      Not checked in the free run.

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

    Interpretationreasoning

    The NHEJ protein machinery represents an important failsafe against lethal duplex-altering double-strand breaks.

    “Thus, the NHEJ protein machinery represents an important failsafe against lethal duplex-altering double-strand breaks.”
    Quote in the paperNot a substantial claim

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

    Interpretationnone given

    Interaction between Mdm2 and NHEJ proteins represents a potential avenue for exiting repair factors from repaired DNA.

    “Interaction between Mdm2 and the non-homologous end joining proteins represents a potential avenue for exiting repair factors from repaired DNA.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    DNA polymerase eta (pol H) is involved in global genomic-NER during S-phase.

    “One such Y family member DNA polymerase, pol eta (pol H), is involved in global genomic-NER during S-phase [52].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [52] Auclair, 2010, Requirement for functional DNA polymerase eta in genome-wide repair of UV-induced DNA damage during S phase, DNA Repair source

      Not checked in the free run.

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

    Premisecitation

    MMEJ functions when DNA bases contain a small amount of sequence homology (microhomology), which can be either terminal on broken ends or embedded within the broken piece of DNA.

    “This functions when DNA bases contain a small amount of sequence homology (microhomology), which can be either terminal on broken ends or embedded within the broken piece of DNA.”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Yun, 2009, CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle, Nature source

      Not checked in the free run.

    • cites [71] You, 2009, CtIP links DNA double-strand break sensing to resection, Mol. Cell source

      Not checked in the free run.

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

    Premisecitation

    A recently discovered sub-pathway called microhomology mediated end joining (MMEJ) operates in conjunction with both NHEJ and HR and utilizes CtIP.

    “It is important to note that a recently discovered sub-pathway operates in conjunction with both NHEJ and HR called microhomology mediated end joining (MMEJ) utilizing a protein called CtIP [70,71].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [70] Yun, 2009, CtIP-BRCA1 modulates the choice of DNA double-strand-break repair pathway throughout the cell cycle, Nature source

      Not checked in the free run.

    • cites [71] You, 2009, CtIP links DNA double-strand break sensing to resection, Mol. Cell source

      Not checked in the free run.

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

    Premisecitation

    Autophosphorylation of DNA-PK occurs when bound to specific sequence composition and DNA termini.

    “Autophosphorylation of DNA-PK occurs when bound to specific sequence composition and DNA termini [59,60].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [59] Pawelczak, 2005, Differential activation of DNA-PK based on DNA strand orientation and sequence bias, Nucl. Acids Res source

      Not checked in the free run.

    • cites [60] Pawelczak, 2008, A mechanism for DNA-PK activation requiring unique contributions from each strand of a DNA terminus and implications for microhomology-mediated nonhomologous DNA end joining, Nucl. Acids Res source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    DNA-PK functions to negate the binding of Mdm2 to p53, allowing cell cycle arrest and DNA repair to follow.

    “DNA-PK appears to function to negate the binding of Mdm2 to p53, which allows for cell cycle arrest and DNA repair to follow.”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [72] Mayo, 1997, Mdm-2 phosphorylation by DNA-dependent protein kinase prevents interaction with p53, Cancer Res

      Not checked in the free run.

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

    Premisecitation

    Ku70/Ku80 forms a preformed channel that slides onto DNA termini, causing a conformational change in Ku under both redox and DNA binding conditions.

    “This unique protein forms a preformed channel so that it slides onto the DNA termini, causing a conformational change in Ku under both redox and DNA binding conditions [57,58].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [57] Andrews, 2006, Kinetic analysis of the Ku-DNA binding activity reveals a redox-dependent alteration in protein structure that stimulates dissociation of the Ku-DNA complex, J. Biol. Chem source

      Not checked in the free run.

    • cites [58] Lehman, 2008, DNA-dependent conformational changes in the Ku heterodimer, Biochemistry source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    When Ku70 is ubiquitinated, Bax is active in response to DNA damage that promotes DSBs, and Akt inhibits Bax-mediated apoptosis partially through stabilization of Ku70.

    “When Ku70 is ubiquitinated, Bax was observed to be active in response to DNA damage that promotes DSBs, and Akt inhibits Bax-mediated apoptosis partially through stabilization of Ku70 [73].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [73] Gama, 2009, Hdm2 is a ubiquitin ligase of Ku70-Akt promotes cell survival by inhibiting Hdm2-dependent Ku70 destabilization, Cell Death Differ source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Mdm2 associates with pol eta and targets its turnover when cells are treated with UV radiation.

    “Very recently, Mdm2 was found to associate with pol eta and turnover of this polymerase was targeted by Mdm2 when cells were treated with UV radiation [53].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [53] Jung, 2012, DNA polymerase eta is targeted by Mdm2 for polyubiquitination and proteasomal degradation in response to ultraviolet irradiation, DNA Repair source

      Not checked in the free run.

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

    Interpretationreasoning

    Removal of Ku after NHEJ is finished represents a unique mechanism.

    “Since Ku70 forms a pre-formed channel with the Ku80 subunit translocating down duplex DNA at sites of DSBs, removal of this protein after NHEJ is finished represents a unique mechanism.”
    Quote in the paperNot a substantial claim

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

    Premisecitation

    Nucleotide addition at DNA termini is facilitated by polymerases β, μ, λ.

    “Nucleotide addition is facilitated at these termini by multiple polymerases: β, μ, λ [64].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [64] Ramsden, 2011, Polymerases in nonhomologous end joining: Building a bridge over broken chromosomes, Antioxid. Redox Signal source

      Not checked in the free run.

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

    Premisecitation

    Artemis utilizes a 5′ exonuclease and a 5′-3′ endonuclease to manipulate ssDNA overhangs for end processing.

    “Artemis utilizes a 5′ exonuclease and a 5′–3′ endonuclease to manipulate ssDNA overhangs for end processing [62,63].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [62] Ma, 2002, Hairpin opening and overhang processing by an Artemis/DNA-dependent protein kinase complex in nonhomologous end joining and V(D)J recombination, Cell source

      Not checked in the free run.

    • cites [63] Pannicke, 2004, Functional and biochemical dissection of the structure-specific nuclease ARTEMIS, EMBO J source

      Not checked in the free run.

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

    Premisecitation

    NHEJ can be divided into four steps: recognition of DNA ends, synaptic complex formation, DNA end processing by nucleases, and ligation of DNA termini.

    “NHEJ can be divided into four steps: recognition of DNA ends, synaptic complex formation, DNA end processing by nucleases, and ligation of DNA termini [55,56].”
    Quote in the paperNot a substantial claim0 of 2 sources checked
    • cites [55] Weterings, 2008, The endless tale of non-homologous end-joining, Cell Res source

      Not checked in the free run.

    • cites [56] Pawelczak, 2011, Coordination of DNA-PK activation and nuclease processing of DNA termini in NHEJ, Antioxid. Redox Signal source

      Not checked in the free run.

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

    Premisecitation

    The NHEJ process is regulated by protein-protein interactions such as Ku/Ligase IV-XRCC4/polymerase μ.

    “This entire process is regulated by protein-protein interactions such as the one formed by Ku/Ligase IV-XRCC4/polymerase μ [65].”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [65] Mahajan, 2002, Association of DNA polymerase mu (pol mu) with Ku and ligase IV: Role for pol mu in end-joining double-strand break repair, Mol. Cell Biol source

      Not checked in the free run.

34 of 34

  • The paper relies on this without support.

    Accumulation of DNA damage and the inability to repair damage or repair gone awry directs human cells towards a tumorigenic phenotype, which is accompanied by cellular degeneration and finally cancer.

    “Accumulation of DNA damage and the inability to repair damage or repair gone awry directs human cells towards a tumorigenic phenotype, which is accompanied by cellular degeneration and finally cancer.”

  • The paper relies on this without support.

    During neoplastic development, disregulated DNA repair pathways play a role in genomic instability, missense mutations and chromosomal deletions and translocations.

    “During neoplastic development, disregulated DNA repair pathway play a role in genomic instability, missense mutations and chromosomal deletions and translocation.”

  • The paper relies on this without support.

    Mdm2 is found in the nucleus during genotoxic stress.

    “What remains unclear is how oncoproteins such as Mdm2 may play a role in preventing or promoting these genomic alterations as Mdm2 has been found in the nucleus during genotoxic stress.”
3 of 3

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References 76 · Cited by 9

Authors
Lehman, J., & Mayo, L.
Affiliations
Department of Pediatrics, Herman B Wells Center for Pediatrics Research, 1044 West Walnut Street, Indianapolis, IN 46202, USA
Corresponding author
Mayo, Lindsey
ORCID
Mayo, Lindsey
Venue
International Journal of Molecular Sciences
Publisher
MDPI AG
Published
2012-12-03
Volume
13
Issue
12
Pages
16373-16386
ISSN
1422-0067 (ISSN-L)
DOI
10.3390/ijms131216373
PMC
PMC3546695
OpenAlex
W2066864190
Semantic Scholar
8ee92989f0376ca3206d75684ad04dd7eb13277c
Cited by
9
References
76
Citations by year
2025: 1 · 2024: 1 · 2023: 1 · 2021: 1 · 2020: 1 · 2019: 1 · 2016: 1 · 2014: 1 · 2013: 1
FWCI
0.07
Type
journal article
Language
en
Open access
Licence
Locations
  • International Journal of Molecular Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • IUScholarWorks (Indiana University) (submittedVersion, cc-by)
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 › Heat shock proteins research
Keywords
MDM2, DNA damage, DNA repair, carcinogenesis, p53, nucleotide excision repair, base excision repair, DNA mismatch repair, non-homologous end joining, homologous recombination, tumor suppressor inactivation, oncogene activation, anticancer agents, tumor progression, cell proliferation
MeSH terms
Animals, DNA Damage, DNA Repair, Humans, Signal Transduction, Proto-Oncogene Proteins c-mdm2, DNA Mismatch Repair, Homologous Recombination, Carcinogenesis

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.

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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