Mdm2 Binds to Nbs1 at Sites of DNA Damage and Regulates Double Strand Break Repair

Alt, Jodi R.; Bouska, Alyssa; Fernandez, Mario R.; Cerny, Ronald L.; Xiao, Hua; Eischen, Christine M.

doi:10.1074/jbc.m413387200

Cited by 103 publications

(158 citation statements)

References 56 publications

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“…Although the exact mechanism of these DNA breaks is still unknown, inhibition of p53 due to increased levels of Mdm2 could lead to DNA instability. However, we have recently determined that overexpression of Mdm2 inhibited DNA double-strand break repair independent of p53 and possibly through its interactions with Nbs1, a component of a DNA repair complex (Alt et al, 2005). c-Myc overexpression, on the other hand, has been shown to induce DNA double-strand breaks rather than inhibit their repair (Vafa et al, 2002).…”

Section: Discussionmentioning

confidence: 99%

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

et al. 2007

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Mdm2, a regulator of the p53 tumor suppressor, is frequently overexpressed in lymphomas, including lymphomas that have inactivated p53. However, the biological consequences of Mdm2 overexpression in lymphocytes are not fully resolved. Here, we report that increased expression of Mdm2 in B cells augmented proliferation and reduced susceptibility to p53-dependent apoptosis, which was due to inhibition of p53 and suppression of p21 expression. Notably, developing and mature B cells from Mdm2 transgenic mice had an increased frequency of chromosomal/chromatid breaks and/or aneuploidy. This Mdm2-mediated genome instability occurred at a similar frequency as that in B cells overexpressing the oncogene c-Myc, but the chromosomal instability was not further enhanced when Mdm2 and c-Myc were overexpressed together. Elevated Mdm2 expression alone increased the occurrence of B-cell transformation in vivo and cooperated with c-Myc overexpression, resulting in an acceleration of B-cell lymphomagenesis. In addition, the frequency of p53 mutations was reduced, but not eliminated, in lymphomas arising in Mdm2/Emu-myc double transgenic mice. Therefore, increased Mdm2 expression facilitated B-cell lymphomagenesis, in part, through regulation of p53 by altering B-cell proliferation and susceptibility to apoptosis, and by inducing chromosomal instability

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Section: Discussionmentioning

confidence: 99%

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

et al. 2007

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“…Taken together these studies suggest that a deficiency in Mdm2 has both ARF and p53-independent consequences during transformation and that Mdm2 has functions independent of p53 during tumor development. It is likely that the interaction of Mdm2 with one or more of the other proteins to which it has been shown to bind (reviewed in Iwakuma and Lozano, 2003), such as the DNA repair protein Nbs1 we recently identified (Alt et al, 2005), is likely responsible for the p53-independent functions of Mdm2 that contribute to tumor development. Therefore, since a haploinsufficiency in Mdm2 may have both p53-dependent and p53-independent effects on tumorigenesis, further investigation is needed to define these pathways.…”

Section: Discussionmentioning

confidence: 99%

Decreased Mdm2 expression inhibits tumor development induced by loss of ARF

et al. 2006

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The tumor suppressor p14/p19 ARF regulates Mdm2, which is known for controlling the p53 tumor suppressor. Here we report that loss of one allele of Mdm2 in cells that lack ARF resulted in a decreased rate of proliferation, fewer chromosomal aberrations, and suppression of Ras-induced transformation. Moreover, a haploinsufficiency of Mdm2 inhibited spontaneous tumor development in ARF-null mice. Remarkably, Mdm2 þ /À ARF À/À mice survived an average of 6 months longer than Mdm2 þ / þ ARF À/À mice. The spectrum of tumors that arose in Mdm2 þ /À ARF À/À mice did not significantly differ from those that developed in mice lacking only ARF. However, the extended tumor latency allowed for the emergence of multiple primary tumors in a third of the Mdm2 þ /À ARF À/À mice, as compared to the single tumor type that arose in ARFnull only mice. Therefore, a decrease in Mdm2 levels restored regulation of critical cellular processes that are altered during transformation and that occur in the absence of ARF. Our findings also indicate that Mdm2 can function independently from ARF and imply that targeting Mdm2 in tumors that lack ARF expression should be an effective therapeutic approach.

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“…MRN plays an essential role during normal DNA replication and prevents the accumulation of broken replication forks. [35][36][37] Our current results suggest that p30 prevents the accumulation of Nbs1 and Rad50 into DSB foci upon irradiation, suggesting that p30 blocks the sensing of DNA damage. As a DSB-specific "guardian of the genome," the MRN complex may in part function in the suppression of transformation.…”

mentioning

confidence: 80%

Human T-lymphotropic type 1 virus p30 inhibits homologous recombination and favors unfaithful DNA repair

Baydoun

Pancewicz

Nicot

2011

Blood

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IntroductionHomologous recombination (HR) is a major pathway of doublestrand break (DSB) repair in mammalian cells. 1 Faithful recombination is critical to avoid genetic and genomic aberrations, and involves a complex and orderly assembly of many checkpoints and repair factors. DSBs frequently occur as a result of exposure to irradiation and chemicals. In response to DSBs, activation of ataxia telangiectasia mutated (ATM) initiates a cascade of events, including phosphorylation of histone H2AX (referred to as ␥-H2AX) and downstream effectors such as structural chromosome maintenance 1 (SCM1) and checkpoint kinase 2 (Chk2). 2,3 Chk2 phosphorylates p53, disrupting its interaction with Mdm2 and stabilizing the p53 protein, 4 which pauses the cell cycle so that the cell can attempt to repair its damaged DNA. H2AX phosphorylation plays an important role in both DNA-damage-checkpoint activation and deactivation of the checkpoint signal to allow the cell cycle to resume. HR is very important during DNA replication in the S phase, when DSBs are generated during lagging strand synthesis or when unrepaired lesions cause replication-fork stalling. 5,6 Initiation of HR involves the recruitment of the MRE11/RAD50/NBS1 (MRN) complex to DNA-damaged sites that can be visualized by accumulation of ␥-H2AX as foci. 7 In contrast, DSBs created during the G1 or M phase are preferentially repaired by a nonconservative, nonhomologous-endjoining (NHEJ) pathway. The NHEJ pathway has been shown to be Ku80 and DNA-dependent protein kinase (DNA-PK) dependent. 8 The switch from HR to NHEJ has not been fully elucidated, but can in part be explained by the fact that MRE11-resection activity generates single-stranded DNA for which Ku80 has a poor affinity, allowing for the assembly of the MRN complex and HR repair. Therefore, regulation of DSB access to MRE11 or Ku80 is likely decisive in the fate and type of DNA repair.HTLV-1 is a human retrovirus associated with adult T-cell leukemia/lymphoma, an aggressive disease with a dismal prognosis. 9 Whereas the majority of HTLV-1-infected individuals remain asymptomatic, upwards of 5% of patients ultimately develop adult T-cell leukemia/lymphoma. The molecular mechanisms of HTLV-1 oncogenesis are poorly understood. HTLV-1 disrupts cell-cycle checkpoints, tumor suppressors, and Notch signaling and reactivates telomerase. [10][11][12][13] Unlike animal oncoretroviruses, HTLV-1 does not transduce a protooncogene and does not integrate at specific sites in the human genome, thereby excluding insertional mutagenesis. The end of the HTLV-1 proviral genome encodes for the regulatory proteins p12, p30, and the HTLV-1 bZIP factor (HBZ), which are involved in virus infectivity, immune escape, and establishment of latency. 14-17 HTLV-1 leukemic cells often present numerous genomic alterations, but the genesis and contribution of these chromosomal defects are presently unclear. The viral oncoprotein Tax plays an important role in the initiation of cellular transformation. In addition, several studies have shown...

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Mdm2 Binds to Nbs1 at Sites of DNA Damage and Regulates Double Strand Break Repair

Cited by 103 publications

References 56 publications

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

Elevated Mdm2 expression induces chromosomal instability and confers a survival and growth advantage to B cells

Decreased Mdm2 expression inhibits tumor development induced by loss of ARF

Human T-lymphotropic type 1 virus p30 inhibits homologous recombination and favors unfaithful DNA repair

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