Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells

Rass, Emilie; Grabarz, Anastazja; Plo, Isabelle; Gautier, Jean; Bertrand, Pascale; Lopez, Bernard S.

doi:10.1038/nsmb.1641

Cited by 276 publications

(323 citation statements)

References 60 publications

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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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“…and CtIP, are involved in MMEJ [25][26][27][28]. Indeed, Zhang and Jasin reported that CtIP depletion decreases translocation frequency both in wild-type and KU70(-/-) murine ES cells [29].…”

Section: Atm Suppresses Dicentric Frequency In the Same Pathway As Dnmentioning

confidence: 99%

Mode of ATM-dependent suppression of chromosome translocation

Yamauchi

Suzuki

Oka

et al. 2011

Biochemical and Biophysical Research Communications

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It is well documented that deficiency in ataxia telangiectasia mutated (ATM) protein leads to elevated frequency of chromosome translocation, however, it remains poorly understood how ATM suppresses translocation frequency. In the present study, we addressed the mechanism of ATM-dependent suppression of translocation frequency. To know frequency of translocation events in a whole genome at once, we performed centromere/telomere FISH and scored dicentric chromosomes, because dicentric and translocation occur with equal frequency and by identical mechanism. By centromere/telomere FISH analysis, we confirmed that chemical inhibition orRNAi-mediated knockdown of ATM causes 2~2.5-fold increase in dicentric frequency at first mitosis after 2 Gy of gamma-irradiation in G0/G1. The FISH analysis revealed that ATM/p53-dependent G1 checkpoint suppresses dicentric frequency, since RNAi-mediated knockdown of p53 elevated dicentric frequency by 1.5-fold. We found ATM also suppresses dicentric occurrence independently of its checkpoint role, as ATM inhibitor showed additional effect on dicentric frequency in the context of p53 depletion and Chk1/2 inactivation. Epistasis analysis using chemical inhibitors revealed that ATM kinase functions in the same pathway that requires kinase activity of DNA-dependent protein kinase catalytic subunit (DNA-PKcs) to suppress dicentric frequency. From the results in the present study, we conclude that ATM minimizes translocation frequency through its commitment to G1 checkpoint and DNA double-strand break repair pathway that requires kinase activity of DNA-PKcs.

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“…The MRN complex is also thought to participate in ATR-CHK1 kinase activation by facilitating DNA end resection [14][15][16][17][18]. It participates in multiple downstream pathways for checkpoint signaling, DNA replication, telomere maintenance, nonhomologous end joining and meiotic recombination [19][20][21][22][23][24].…”

Section: Introductionmentioning

confidence: 99%

The MRE11 GAR motif regulates DNA double-strand break processing and ATR activation

Vogel

Coulombe

et al. 2011

Cell Res

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The MRE11/RAD50/NBS1 complex is the primary sensor rapidly recruited to DNA double-strand breaks (DSBs). MRE11 is known to be arginine methylated by PRMT1 within its glycine-arginine-rich (GAR) motif. In this study, we report a mouse knock-in allele of Mre11 that substitutes the arginines with lysines in the GAR motif and generates the MRE11 RK protein devoid of methylated arginines. The Mre11 RK/RK mice were hypersensitive to γ-irradiation (IR) and the cells from these mice displayed cell cycle checkpoint defects and chromosome instability. Moreover, the Mre11 RK/RK MEFs exhibited ATR/CHK1 signaling defects and impairment in the recruitment of RPA and RAD51 to the damaged sites. The M RK RN complex formed and localized to the sites of DNA damage and normally activated the ATM pathway in response to IR. The M RK RN complex exhibited exonuclease and DNA-binding defects in vitro responsible for the impaired DNA end resection and ATR activation observed in vivo in response to IR. Our findings provide genetic evidence for the critical role of the MRE11 GAR motif in DSB repair, and demonstrate a mechanistic link between post-translational modifications at the MRE11 GAR motif and DSB processing, as well as the ATR/ CHK1 checkpoint signaling.

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Role of Mre11 in chromosomal nonhomologous end joining in mammalian cells

Cited by 276 publications

References 60 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

Mode of ATM-dependent suppression of chromosome translocation

The MRE11 GAR motif regulates DNA double-strand break processing and ATR activation

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