Distinct Roles of Chromatin-Associated Proteins MDC1 and 53BP1 in Mammalian Double-Strand Break Repair

Xie, Anyong; Hartlerode, Andrea J.; Stucki, Manuel; Odate, Shobu; Puget, Nadine; Kwok, Amy Ho Yan; Nagaraju, Ganesh; Yan, Catherine T.; Alt, Frederick W.; Chen, Junjie; Jackson, Stephen; Scully, Ralph

doi:10.1016/j.molcel.2007.12.005

Cited by 201 publications

(224 citation statements)

References 48 publications

(66 reference statements)

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“…To this end, we utilized cell lines that contain stably integrated reporters to assess the rates of HR (DR-GFP 10,11 ) and NHEJ. 12 --14 For NHEJ, we used cell lines containing two types of NHEJ-reporter substrates; the pCOH-CD4 that permits analysis of the NHEJ of two distal ends (separated by 3.2 kb), 12,13 and a GFP-based substrate, 14 to measure the NHEJ on closely adjacent ends, separated by only 34 bp. 14 Figure 1.…”

Section: Resultsmentioning

confidence: 99%

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

et al. 2012

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DNA repair is essential in maintaining genome integrity and defects in different steps of the process have been linked to cancer and aging. It is a long lasting question how DNA repair is spatially and temporarily organized in the highly compartmentalized nucleus and whether the diverse nuclear compartments regulate differently the efficiency of repair. Increasing evidence suggest the involvement of nuclear pore complexes in repair of double-strand breaks (DSBs) in yeast. Here, we show that the human nucleoporin 153 (NUP153) has a role in repair of DSBs and in the activation of DNA damage checkpoints. We explore the mechanism of action of NUP153 and we propose its potential as a novel therapeutic target in cancers.Oncogene ( Keywords: DNA repair; nuclear pore; 53BP1 INTRODUCTION DNA double-strand breaks (DSBs) are particularly dangerous as their inefficient or inaccurate repair can result in mutations and chromosomal translocations that may induce cancer. 1 DSBs can be repaired by one of two major pathways: homology-based repair (homologous recombination (HR)) using the intact chromatid as a template present in proximity in S and G2 phases of the cell cycle, or direct joining across the break site (non-homologous end joining (NHEJ)). 2 The coordination between cell cycle progression and DSB repair (DSBR) is regulated by the DNA damage response (DDR) signalling pathway, which activates the cell cycle checkpoints in the presence of DNA breaks. 3 This pathway is initiated by the recruitment of the MRN (MRE11 --RAD50 --NBS1) sensor complex to sites of damage. The recruitment of MRN subsequently activates the ATM kinase, which associates with DSBs and phosphorylates the histone variant H2AX (g-H2AX). 2 MDC1 can then bind to gH2AX and recruit new MRN and ATM proteins, leading to spreading of the repair machinery along the chromosome. MDC1 also recruits ubiquitin ligases, such as RNF8 and RNF168, which facilitate the recruitment of the downstream factors 53BP1 and BRCA1. 2 When the DNA is resected to singlestranded DNA, it is recognized by replication protein A, which results in the recruitment of ATR. 2 Both the ATM and the ATR dependent branches of the pathway lead to the activation of the checkpoint kinases, CHK1 and CHK2, which stall damaged cells in their cell cycle until the lesions are resolved. 3 DNA repair, like all DNA-dependent processes, occur in the highly compartmentalized nucleus. Most nuclear events do not occur ubiquitously, but are limited to defined sites. 2 Several studies in yeast have shown that dedicated DNA repair centres exist as preferential sites of repair. 2,4 Furthermore, persistent DSBs in yeast migrate from their internal nuclear positions to the nuclear periphery, where they associate with nuclear pores. 5,6 This sequestration to the nuclear periphery was shown to require

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Section: Resultsmentioning

confidence: 99%

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

et al. 2012

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“…This observation is consistent with previous linkage between 53BP1 and NHEJ that 53BP1 mainly functions in NHEJ repair pathway. 55,56 How BZLF1 disrupts NHEJ is not clear at this stage. BZLF1 has been reported to bind to Ku80 through its C-terminal region.…”

Section: Discussionmentioning

confidence: 97%

Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

Yang

Deng

Hau

et al. 2015

Laboratory Investigation

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Epstein-Barr virus (EBV) infection is closely associated with several human malignancies including nasopharyngeal carcinoma (NPC). The EBV immediate-early protein BZLF1 is the key mediator that switches EBV infection from latent to lytic forms. The lytic form of EBV infection has been implicated in human carcinogenesis but its molecular mechanisms remain unclear. BZLF1 has been shown to be a binding partner of several DNA damage response (DDR) proteins. Its functions in host DDR remain unknown. Thus, we explore the effects of BZLF1 on cellular response to DNA damage in NPC cells. We found that expression of BZLF1 impaired the binding between RNF8 and MDC1 (mediator of DNA damage checkpoint 1), which in turn interfered with the localization of RNF8 and 53BP1 to the DNA damage sites. The RNF8-53BP1 pathway is important for repair of DNA double-strand breaks and DNA damage-induced G2/M checkpoint activation. Our results showed that, by impairing DNA damage repair as well as abrogating G2/M checkpoint, BZLF1 induced genomic instability and rendered cells more sensitive to ionizing radiation. Moreover, the blockage of 53BP1 and RNF8 foci formation was recapitulated in EBV-infected cells. Taken together, our study raises the possibility that, by causing mis-localization of important DDR proteins, BZLF1 may function as a link between lytic EBV infection and impaired DNA damage repair, thus contributing to the carcinogenesis of EBV-associated human epithelial malignancies. Epstein-Barr virus (EBV) is a gamma herpesvirus and infection with EBV is associated with a variety of epithelial and B-cell cancers. 1,2 EBV has a biphasic life cycle consisting of latent and lytic stages. The switch from latent to lytic infection is triggered by the EBV immediate-early transcription factor, BZLF1 (ZEBRA, Zta, Z, EB1). 3,4 A number of reports have demonstrated that lytic EBV activation is intimately linked to the pathogenesis of EBV-induced malignancies including the development of NPC. [5][6][7][8] The mammalian DNA damage response (DDR) network has pivotal roles in maintaining genome stability and tumor suppression. [9][10][11][12][13] In the presence of double-strand break (DSBs), the protein complex composed of MRE11-RAD50-NBS1 (MRN) recruits and activates the ataxia-telangiectasiamutated (ATM) kinase at the vicinity of DSBs, 10 which leads to the phosphorylation of the histone variant H2AX (γH2AX). γH2AX decorates chromatin domains flanking DSBs, and is directly engaged by the mediator of DNA damage checkpoint 1 (MDC1). MDC1 loading onto the damaged chromatin subsequently permits the productive accumulation of a cohort of DNA damage signaling and mediator proteins. 14,15 In particular, the RING finger ubiquitin ligase RNF8 is targeted to MDC1 via its phospho-binding forkheadassociated domain, where it initiates a cascade of chromatin ubiquitination events important for tethering of DNA damage mediator and repair proteins, including 53BP1 and BRCA1, [16][17][18][19] the dysregulation of which compromises genome stability and cont...

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“…55 Another report describes the role of H4K20me during NHEJ in mammals, whereby during the process of XRCC4-dependent NHEJ, 53BP1 recruitment depends on its interaction with dimethylated H4K20 but not on H2AX. 23 The same study also found that, alternatively, MDC1 mediates efficient HR/SCR (sister-chromatid recombination) in a manner strictly dependent on its ability to recruit γH2AX and does not require recruitment of 53BP1 or BRCA1. Therefore, these results shed light on how distinct histone tail-protein interactions promote engagement of different DSB pathways.…”

Section: Chromatin Remodeling Activities During Dna Repairmentioning

confidence: 84%

“…20 The cooperative interaction of NBS1 and ATM facilitates the further recruitment of other DNA damage response proteins, such as the mediators MDC1 (mediator of DNA damage checkpoint protein 1), 53BP1 (p53-binding protein 1) and BRCA1 (breast cancer susceptibility gene 1). [21][22][23] Remarkably, histone phosphorylation, methylation and ubiquitination cooperate in the recruitment of MDC1, 53BP1 and BRAC1, which act as adaptor proteins for recruiting additional members of the DNA damage response to sites of DNA lesions and for introducing them to the transducer kinases. All three factors share common structural features; they contain two consecutive BRCT domains (BRCA1 C-terminal domains), known as tandem BRCT domains, which are phosphoprotein-binding modules found in many proteins that regulate the DNA damage response.…”

confidence: 99%

Chromatin dynamics coupled to DNA repair

Huertas

Sendra²,

Muñoz³

2009

Epigenetics

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In order to protect and preserve the integrity of the genome, eukaryotic cells have developed accurate DNA repair pathways involving a coordinated network of DNA repair and epigenetic factors. The DNA damage response has to proceed in the context of chromatin, a packaged and compact structure that is flexible enough to regulate the accession of the DNA repair machinery to DNA-damaged sites. Chromatin modifications and ATP-remodeling activities are both necessary to ensure efficient DNA repair. Here we review the current progress of research into the importance of chromatin modifications and the ATP-remodeling complex to the DNA damage response, with respect to the sensing and signaling of DNA lesions, DNA repair and the processes that restore chromatin structure.

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Distinct Roles of Chromatin-Associated Proteins MDC1 and 53BP1 in Mammalian Double-Strand Break Repair

Cited by 201 publications

References 48 publications

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

The nucleoporin 153, a novel factor in double-strand break repair and DNA damage response

Epstein–Barr virus BZLF1 protein impairs accumulation of host DNA damage proteins at damage sites in response to DNA damage

Chromatin dynamics coupled to DNA repair

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