DNA double strand break repair pathway choice: a chromatin based decision?

Clouaire, Thomas; Legube, Gaëlle

doi:10.1080/19491034.2015.1010946

Cited by 100 publications

(83 citation statements)

References 60 publications

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“…It is now well established that the local chromatin structure can influence how a given DSB is handled and subsequently repaired (for review, see Clouaire and Legube, 2015). We thus set out to understand the contribution of chromatin to repair pathway choice by defining chromatin states favorable to HR and NHEJ.…”

Section: Resultsmentioning

confidence: 99%

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Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

et al. 2018

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SummaryDouble-strand breaks (DSBs) are extremely detrimental DNA lesions that can lead to cancer-driving mutations and translocations. Non-homologous end joining (NHEJ) and homologous recombination (HR) represent the two main repair pathways operating in the context of chromatin to ensure genome stability. Despite extensive efforts, our knowledge of DSB-induced chromatin still remains fragmented. Here, we describe the distribution of 20 chromatin features at multiple DSBs spread throughout the human genome using ChIP-seq. We provide the most comprehensive picture of the chromatin landscape set up at DSBs and identify NHEJ- and HR-specific chromatin events. This study revealed the existence of a DSB-induced monoubiquitination-to-acetylation switch on histone H2B lysine 120, likely mediated by the SAGA complex, as well as higher-order signaling at HR-repaired DSBs whereby histone H1 is evicted while ubiquitin and 53BP1 accumulate over the entire γH2AX domains.

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Section: Resultsmentioning

confidence: 99%

“…Inaccuracy, failure, or misuse of each of these pathways can trigger very different consequences on the genome. DSB repair pathway choice can be influenced by cell cycle phase (Hustedt and Durocher, 2016), DNA end complexity (Schipler and Iliakis, 2013), and the type of damaged locus (Clouaire and Legube, 2015, Engel et al., 2018). …”

Section: Introductionmentioning

confidence: 99%

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

et al. 2018

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“…Emerging evidence has suggested that chromatin state influences DSB repair 64 . Accordingly, the ability of deprotected telomeres to successfully carry out repair by NHEJ also partly depends on chromatin factors.…”

Section: Regulation Of Telomere Fusionsmentioning

confidence: 99%

Complex interactions between the DNA-damage response and mammalian telomeres

Arnoult

Karlseder

2015

Nat Struct Mol Biol

184

168

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Natural chromosome ends resemble double-stranded DNA breaks, but they do not activate a damage response in healthy cells. Telomeres therefore have evolved to solve the ‘end-protection problem’ by inhibiting multiple DNA damage–response pathways. During the past decade, the view of telomeres has progressed from simple caps that hide chromosome ends to complex machineries that have an active role in organizing the genome. Here we focus on mammalian telomeres and summarize and interpret recent discoveries in detail, focusing on how repair pathways are inhibited, how resection and replication are controlled and how these mechanisms govern cell fate during senescence, crisis and transformation.

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“…Importantly this pathway is strongly suppressed during the G1 cell cycle phase, most likely to minimize the use of an illegitimate copy as a template19. Besides the tight control exerted by the cell cycle stage on repair pathway usage, a growing body of evidence suggests that repair is also regulated by chromatin and varies across the genome (reviewed in20). High resolution profiles of RAD51 and XRCC4 (involved respectively in HR and NHEJ), on a genome wide scale, following induction of multiple, sequence-specific, DSBs by a restriction enzyme (AsiSI) revealed that, in post-replicative cells, DSBs lying in intergenic regions or silent genes are mostly repaired by NHEJ, while those occurring in active genes are channeled to HR21.…”

Section: Introductionmentioning

confidence: 99%

Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes

Aymard

Aguirrebengoa

Guillou

et al. 2017

Nat Struct Mol Biol

238

277

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The ability of DNA Double Strand Breaks (DSBs) to cluster in mammalian cells has been subjected to intense debate over the past few years. Here we used a high throughput chromosome conformation capture assay (Capture Hi-C) to investigate clustering of DSBs induced at defined loci in the human genome. We unambiguously found that DSBs do cluster but only when induced in transcriptionally active genes. Clustering of damaged genes mainly occurs during the G1 cell cycle phase and coincides with delayed repair. Moreover DSB clustering depends on the MRN complex, as well as the Formin 2 (FMN2) nuclear actin organizer and the LINC (LInker of Nuclear and Cytoplasmic skeleton) complex, suggesting that active mechanisms promote DSB clustering. This work reveals that when damaged, active genes exhibit a very peculiar behavior compared to the rest of the genome, being mostly left unrepaired and clustered in G1 while being repaired by homologous recombination in post-replicative cells.

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DNA double strand break repair pathway choice: a chromatin based decision?

Cited by 100 publications

References 60 publications

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

Comprehensive Mapping of Histone Modifications at DNA Double-Strand Breaks Deciphers Repair Pathway Chromatin Signatures

Complex interactions between the DNA-damage response and mammalian telomeres

Genome-wide mapping of long-range contacts unveils clustering of DNA double-strand breaks at damaged active genes

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