53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks

Bunting, Samuel F.; Callén, Elsa; Wong, Nancy; Chen, Hua Tang; Polato, Federica; Gunn, Amanda; Bothmer, Anne; Feldhahn, Niklas; Fernández-Capetillo, Óscar; Cao, Liu; Xu, Xiaoling; Deng, Chu Xia; Finkel, Toren; Nussenzweig, Michel C.; Stark, Jeremy M.; Nussenzweig, André

doi:10.1016/j.cell.2010.03.012

Cited by 1,489 publications

(1,722 citation statements)

References 68 publications

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“…18,19 These studies have placed 53BP1 as a top candidate for pharmacological targeting for future breast cancer therapies. Therefore, we sought to understand whether the impairment of 53BP1 is sufficient to explain the NUP153-deficient phenotype in our DNA repair assays, to suggest NUP153 as a potential candidate for targeted cancer therapy.…”

Section: Resultsmentioning

confidence: 99%

“…However, as NUP153 promotes 53BP1 IRIF foci formation after DNA damage, impairment of NUP153 in BRCA1 cancer cells could mimic the phenotype of 53BP1 depletion, rescuing lethality and conferring resistance to PARP inhibition. 18,19 It will be consequently very interesting to exploit in the future the potential of NUP153 as a therapeutic target in certain cancers. were subjected to laser micro-irradiation using a 800-nm laser and subsequent real time recording of protein assembly at the damaged area.…”

Section: Resultsmentioning

confidence: 99%

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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%

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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“…53BP1 is a key determinant of DSB repair pathway choice and directs DNA repair toward NHEJ by competition with the cell cycle‐regulated HR repair protein BRCA1 (Bunting et al , 2010). Accordingly, 53BP1 deletion in BRCA1‐deficient cells allows replication protein A (RPA) loading and restoration of HR.…”

Section: Discussionmentioning

confidence: 99%

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

et al. 2016

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Sirtuins, a family of protein deacetylases, promote cellular homeostasis by mediating communication between cells and environment. The enzymatic activity of the mammalian sirtuin SIRT7 targets acetylated lysine in the N‐terminal tail of histone H3 (H3K18Ac), thus modulating chromatin structure and transcriptional competency. SIRT7 deletion is associated with reduced lifespan in mice through unknown mechanisms. Here, we show that SirT7‐knockout mice suffer from partial embryonic lethality and a progeroid‐like phenotype. Consistently, SIRT7‐deficient cells display increased replication stress and impaired DNA repair. SIRT7 is recruited in a PARP1‐dependent manner to sites of DNA damage, where it modulates H3K18Ac levels. H3K18Ac in turn affects recruitment of the damage response factor 53BP1 to DNA double‐strand breaks (DSBs), thereby influencing the efficiency of non‐homologous end joining (NHEJ). These results reveal a direct role for SIRT7 in DSB repair and establish a functional link between SIRT7‐mediated H3K18 deacetylation and the maintenance of genome integrity.

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“…In line with this hypothesis, HP1α knockdown impairs both 53BP1 and BRCA1 recruitment to sites of damage. 17 Given that 53BP1 and BRCA1 have opposite effects on DNA-end resection, [30][31][32][33] further research on this particular issue would certainly be critical to shed light on the molecular details of HP1 role during this process.…”

Section: Discussionmentioning

confidence: 99%

Differential contribution of HP1 proteins to DNA end resection and homology-directed repair

Soria

Almouzni

2013

Cell Cycle

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53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks

Cited by 1,489 publications

References 68 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

SIRT 7 promotes genome integrity and modulates non‐homologous end joining DNA repair

Differential contribution of HP1 proteins to DNA end resection and homology-directed repair

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