FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51

Chu, Wai Kit; Payne, Miranda; Beli, Petra; Hanada, Katsuhiro; Choudhary, Chunaram; Hickson, Ian D.

doi:10.1038/ncomms6931

Cited by 59 publications

(50 citation statements)

References 49 publications

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“…Srs2 is required for Rad51 removal in yeast, UvrD is a bacterial structural homolog, and RTEL1 and RECQ5 have been suggested as functional homologs in Caenorhabditis elegans and mammals (Barber et al , 2008; Schwendener et al , 2010). FBH1 helicase is also a strong candidate for the role of Srs2 in mammals as it shares more structural similarity with Srs2 than RTEL1 and RECQ5 and has been shown to regulate RAD51 (Chu et al , 2015). Identifying human functional homolog for the role of Srs2 in restoration of resected DNA might improve not only our understanding of genome stability mechanisms and but also human diseases stemming from defects in genome maintenance.…”

Section: Discussionmentioning

confidence: 99%

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

et al. 2017

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Cells use homology‐dependent DNA repair to mend chromosome breaks and restore broken replication forks, thereby ensuring genome stability and cell survival. DNA break repair via homology‐based mechanisms involves nuclease‐dependent DNA end resection, which generates long tracts of single‐stranded DNA required for checkpoint activation and loading of homologous recombination proteins Rad52/51/55/57. While recruitment of the homologous recombination machinery is well characterized, it is not known how its presence at repair loci is coordinated with downstream re‐synthesis of resected DNA. We show that Rad51 inhibits recruitment of proliferating cell nuclear antigen (PCNA), the platform for assembly of the DNA replication machinery, and that unloading of Rad51 by Srs2 helicase is required for efficient PCNA loading and restoration of resected DNA. As a result, srs2Δ mutants are deficient in DNA repair correlating with extensive DNA processing, but this defect in srs2Δ mutants can be suppressed by inactivation of the resection nuclease Exo1. We propose a model in which during re‐synthesis of resected DNA, the replication machinery must catch up with the preceding processing nucleases, in order to close the single‐stranded gap and terminate further resection.

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Section: Discussionmentioning

confidence: 99%

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

et al. 2017

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“…scSrs2 functions by stimulating scRad51 to hydrolyze ATP to ADP, which releases scRad51 from ssDNA (Krejci et al 2003; Veaute et al 2003). In humans, numerous proteins carry out anti-recombinase functions to negatively regulate hRAD51 at both pre- and post-synaptic recombination steps, such as hRTEL, hPARI, hFBH1, and hRECQL5, although their mechanisms of action may differ from scSrs2 (Branzei and Foiani 2007; Bugreev et al 2007; Chu et al 2015; Hu et al 2007; Karpenshif and Bernstein 2012; Mankouri et al 2012; Moldovan et al 2012). These redundant regulatory systems ensure that functional Rad51 filaments form only at sites of damage and not at other, undamaged portions of the genome.…”

Section: Double-strand Break Repair By Homologous Recombinationmentioning

confidence: 99%

Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication

Godin

Sullivan

Bernstein

2016

Biochem. Cell Biol.

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In this review we focus on new insights that challenge our understanding of homologous recombination (HR) and Rad51 regulation. Recent advances using high resolution microscopy and single molecule techniques have broadened our knowledge of Rad51 filament formation and strand invasion at double-strand break (DSB) sites and at replication forks, which are one of most physiologically relevant forms of HR from yeast to humans. Rad51 filament formation and strand invasion is regulated by many mediator proteins such as the Rad51 paralogues and the Shu complex, consisting of a Shu2/SWS1 family member and additional Rad51 paralogues. Importantly, a novel RAD-51 paralogue was discovered in C. elegans and its in vitro characterization has demonstrated a new function for the worm RAD-51 paralogues during HR. Conservation of the human RAD51 paralogues function during HR and repair of replicative damage demonstrate how the RAD51 mediators play a critical role in human health and genomic integrity. Together, these new findings provide a framework for understanding RAD51 and its mediators in DNA repair during multiple cellular contexts.

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“…Phosphorylation of Tyr315 by BCR/ ABL is important for DSB repair and drug resistance, while phosphorylation of Tyr54 by c-Abl inhibits RAD51 binding to DNA and its ATP-dependent DNA strand exchange reaction (Yuan et al 1998;Slupianek et al 2011). FBH1-mediated RAD51 monoubiquitination influences DNA replication fork stability and plays an important role in DNA replication stress (Chu et al 2015). However, the role of ubiquitination/deubiquitination of RAD51 in DSBs is unclear.…”

Section: The Role Of Uchl3 In Response To Parp Inhibition and Irradiamentioning

confidence: 99%

A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination

Luo

et al. 2016

Genes Dev.

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Homologous recombination (HR) is one of the major DNA double-strand break (DSB) repair pathways in mammalian cells. Defects in HR trigger genomic instability and result in cancer predisposition. The defining step of HR is homologous strand exchange directed by the protein RAD51, which is recruited to DSBs by BRCA2. However, the regulation of the BRCA2-RAD51 axis remains unclear. Here we report that ubiquitination of RAD51 hinders RAD51-BRCA2 interaction, while deubiquitination of RAD51 facilitates RAD51-BRCA2 binding and RAD51 recruitment and thus is critical for proper HR. Mechanistically, in response to DNA damage, the deubiquitinase UCHL3 is phosphorylated and activated by ATM. UCHL3, in turn, deubiquitinates RAD51 and promotes the binding between RAD51 and BRCA2. Overexpression of UCHL3 renders breast cancer cells resistant to radiation and chemotherapy, while depletion of UCHL3 sensitizes cells to these treatments, suggesting a determinant role of UCHL3 in cancer therapy. Overall, we identify UCHL3 as a novel regulator of DNA repair and reveal a model in which a phosphorylation-deubiquitination cascade dynamically regulates the BRCA2-RAD51 pathway.

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FBH1 influences DNA replication fork stability and homologous recombination through ubiquitylation of RAD51

Cited by 59 publications

References 49 publications

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

Unloading of homologous recombination factors is required for restoring double‐stranded DNA at damage repair loci

Novel insights into RAD51 activity and regulation during homologous recombination and DNA replication

A phosphorylation–deubiquitination cascade regulates the BRCA2–RAD51 axis in homologous recombination

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