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Defects in DNA damage repair can lead to genomic instability and cancer development. The tumor suppressor gene p53 regulates cell cycle arrest to allow time for DNA repair. The oncoprotein murine double minute 2 (MDM2) promotes cell survival, proliferation, invasion, and therapeutic resistance in many types of cancer. The main role of MDM2 is to inhibit the activity of p53 and promote its degradation. In this review, we describe the effects of MDM2 on genomic instability, the role of MDM2 in p53 release and binding of DNA repair proteins to inhibit repair, and the regulatory network of MDM2, including its transcriptional modifications, protein stability, and localization. DNA damage in the maintenance of genome integrity and control of the MDM2-p53 axis. We also discuss the p53-dependent and p53-oncogenic function of MDM2 and the results of clinical trials using clinical inhibitors targeting p53-MDM2 for the treatment of certain cancers.
What Process Repairs Damage To A Preexisting Double Helix
Genomic instability is a hallmark of cancer and is regulated by the balance between DNA damage and repair (Aguilera and Garcia-Muse, 2013). Consequences of genomic instability include error-prone DNA synthesis, chromosome copy number variations, and chromosomal structural aberrations (Jasin, 2000; Ganem et al., 2007) (Figure 1). Conversely, intact damage can lead to transcription and replication arrest, leading to cell death and senescence (Hoeijmakers, 2009).
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Figure 1 Genomic instability and other effects induced by mouse double minute 2 (MDM2). Oncogene p19 (ARF) interacts with MDM2 to prevent its function. MDM2 can inhibit both p53 and NBS1 to regulate multiple physiological processes and/or induce genomic instability, in which ATM plays a central phosphorylation regulatory role.
To address the threat posed by genomic alterations, cells have evolved a kinase cascade signaling pathway called the DNA damage response (DDR) ( Harper and Elledge, 2007 ). An initial step in an active DDR is the rapid recruitment of DNA repair proteins to damaged sites that serve to recruit downstream factors ( Soutoglou and Misteli, 2010 ). Misregulated DDR can increase the accumulation of unrepaired DNA lesions and lead to aberrant cell proliferation leading to malignancies ( Jackson and Bartek, 2009 ).
The tumor suppressor p53 is recruited directly to sites of DNA damage in both a sequence-specific and non-specific manner to play a protective role in the DDR (Lee et al., 1995; Liu and Kulesz-Martin, 2001) (Figure 1). P53 deficiency results in reduced repair activity and decreased cell survival after UV-induced DNA damage, suggesting the involvement of p53 in nucleotide excision repair (NER) (Smith et al., 1995). P53 is also involved in both global genome-wide NER and transcription-coupled NER by DNA polymerase δ and ε, respectively ( Mirzayans et al., 1996 ). The interaction of p53 with the apyrimidine endonuclease APE1/Ref-1 and the regulatory function of OGG1, MUTYH, and 3-methyladenine DNA glycosylase by p53 all indicate a function of p53 in base excision repair (BER). Among the two major double-strand break repair pathways, p53 interacts with both non-homologous end-joining (NHEJ) and homologous recombination (HR) proteins at the RAD51 promoter to regulate its expression (Williams and Schumacher, 2016). ).
The E3 ligase MDM2 (mouse double minute 2) contains 491 amino acids and is a major negative regulator of p53 (Figure 1). MDM2 controls the activity, subcellular localization, and stability of p53 ( Eischen and Lozano, 2014 ). Increased MDM2 expression is commonly observed in various types of cancer, suggesting its oncogenic function (Eischen and Lozano, 2014). MDM2 interacts with large and diverse substrates through complex structures, post-translational modifications, and diverse isoforms to function as an important hub in various signaling pathways ( Fahraeus and Olivares-Illana, 2014 ). The main role of p53 as a tumor suppressor relies on its transcriptional activity to regulate target genes in a variety of biological pathways (Sullivan et al., 2018). MDM2 binds p53 directly through its N-terminal transactivation domain to inhibit p53 transactivation (Momand et al., 1992; Oliner et al., 1993). MDM2 also forms homodimers to ubiquitinate p53, leading to p53 proteasomal degradation (Haupt et al., 1997; Kubbutat et al., 1997). In this review, we highlight the specific regulatory network of MDM2 in the DDR and discuss the potential clinical applications of MDM2 antagonists and the prospect of developing new combination strategies.
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As a negative regulator of p53, the function of MDM2 in cell survival versus cell death is complex and depends on the extent of DNA damage and repair capacity. An abnormal MDM2-p53 regulatory loop and its corresponding delayed DDR provide an additional layer to control genomic instability. The interaction of MDM2 with p53 and the Mre11-Rad50-Nbs1 complex indicates that MDM2 affects genomic instability in both a p53-dependent and p53-independent manner.
Given that MDM2 binds to p53 to inhibit its transactivation and that it induces p53 protein degradation, it is reasonable to hypothesize that MDM2 directly regulates genomic instability through p53. The oncogene Myc activates the p19 (ARF)-MDM2 pathway to coordinate a p53-dependent checkpoint and apoptotic program (Zindy et al., 1998; Eischen et al., 1999). ARF interacts with MDM2 to direct its degradation and prevents p53/MDM2 negative feedback, thereby preventing p53 degradation (Zhang et al., 1998; Weber et al., 1999). High levels of MDM2 are detected in advanced-stage breast ductal carcinoma and squamous cell carcinoma with wild-type p53. Overexpression of MDM2 and/or deletion or mutation of p53 resulted in centrosome hyperamplification and chromosome instability in these cancer cells (Carroll et al., 1999). A lymphoma transformation study showed that overexpression of MDM2 in B cells resulted in reduced susceptibility to p53-dependent apoptosis through inhibition of p53 and p21 ( Wang et al., 2008 ). MDM2 transgenic mice also showed increased chromosome breaks, chromosome fusions, aneuploidy, and polyploidy ( Lushnikova et al., 2011 ). Disruption of p53 by overexpression of MDM2 has also been shown to activate the S-phase checkpoint to inhibit DNA replication origins, leading to replication fork instability (Frum et al., 2014; Primo and Teixeira, 2019).
MDM2 also affects genomic instability independently of p53. Mammary epithelial cells were found to undergo multiple rounds of S phase without cell division to generate increased polyploidy in response to MDM2 overexpression, regardless of p53 expression levels in mice (Lundgren et al., 1997). The Mre11/Rad50/NBS1 (MRN) complex is a central sensor in the DSBR. Mre11 and NBS1 mutant mice show checkpoint defects and chromosomal instability ( Stracker et al., 2004 ). MDM2 associates with the MRN complex through a direct interaction with NBS1 independent of p53, leading to the recruitment of MDM2 to sites of DNA damage with delayed DNA repair and disruption of DNA integrity ( Alt et al., 2005 ). Interaction of MDM2 with NBS1 inhibits DNA repair and induces chromosome breakage and transformation efficiency in p53-deficient cells ( Bouska et al., 2008 ). With small molecule inhibitors targeting the interaction of p53 with MDM2, a p53-independent function of MDM2 in NBS1 regulation has been found and is worthy of consideration in cancer drug design (Bouska and Eischen, 2009). In addition to binding NBS1, MDM2 promotes the transcription factor HBP1 to promote its degradation, thus preventing the transcriptional inhibition role of HBP1 on its target genes to induce genomic instability such as global DNA hypermethylation and histone hypermethylation (Cao et al. , 2019).
MDM2 is regulated downstream of DNA damage by different mechanisms, such as inactivation by post-translational modification and destruction by p53-MDM2 interaction to relieve p53 inhibition. Increased p53 levels induce cell senescence, cell cycle arrest, and apoptosis. Meanwhile, the interaction of MDM2 with the DNA repair complex MRN exists and is independent of p53 status (Eischen, 2017). Accumulated unprocessed DNA breaks further activate p53 and promote changes such as chromosome translocation, gene fusion, micronucleus enlargement, and gene amplification, which are common causes of cancer malignancy (Morgan et al., 1998; Bunting and Nussenzweig, 2013). . MDM2 is in turn transcriptionally regulated by p53 to form a feedback loop to maintain cellular homeostasis under genetic stress.
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The regulatory function of MDM2 on p53 after DNA damage is complex because it depends on the type of damage, p53 substrates, and different modifications on p53 and MDM2 proteins. A key step in p53 activation following DNA damage and other genetic stress is disruption of the p53-MDM2 interaction and p53 release (Figure 2). The inhibitory role of MDM2 on p53 involves blocking p53 transcriptional activation and regulating p53 protein levels. Disruption of the p53-MDM2 interaction alone is sufficient to stabilize and activate p53 even without DNA damage (Bottger et al., 1997). MDM2 binding sites in the p53 amino terminus overlap with binding sites in p53 that interact with the transcriptional machinery. MDM2 competes with transcription factors such as TFIID and TAFII31 for binding to p53 to block p53-mediated transcription (Lin et al., 1994; Lu and Levine, 1995; Thut et al., 1995). Research has also shown that MDM2 represses the basal transcriptional machinery directly through its inhibitory domain (Thut et al., 1997). NEDD8 has a similar ubiquitination-related modification that can conjugate to p53 in an MDM2-dependent manner to repress p53 transcription ( Xirodimas et al., 2004 ). MDM2 also induces proteasomal degradation of p53. Moreover, expression of MDM2 significantly inhibits the accumulation of p53 after DNA damage. These results indicate post-translational regulation under stress (Haupt et al., 1997; Kubbutat et al., 1997).
Figure 2 Regulation of the p53-mouse double minute 2 (MDM2) axis after DNA damage. Under conditions of DNA damage, both autodegradation of MDM2 and disruption of the p53-MDM2 interaction result in stable and active p53. P53 is also phosphorylated at Ser15 and
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