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PMID: 27348077 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

53BP1 fosters fidelity of homology-directed DNA repair.

Nature structural & molecular biology ·Vol. 23 ·No. 8 ·2016-00-00 ·Pages 714-21

Ochs F, Somyajit K, Altmeyer M, Rask MB, Lukas J, Lukas C

Abstract

Repair of DNA double-strand breaks (DSBs) in mammals is coordinated by the ubiquitin-dependent accumulation of 53BP1 at DSB-flanking chromatin. Owing to its ability to limit DNA-end processing, 53BP1 is thought to promote nonhomologous end-joining (NHEJ) and to suppress homology-directed repair (HDR). Here, we show that silencing 53BP1 or exhausting its capacity to bind damaged chromatin changes limited DSB resection to hyper-resection and results in a switch from error-free gene conversion by RAD51 to mutagenic single-strand annealing by RAD52. Thus, rather than suppressing HDR, 53BP1 fosters its fidelity. These findings illuminate causes and consequences of synthetic viability acquired through 53BP1 silencing in cells lacking the BRCA1 tumor suppressor. We show that such cells survive DSB assaults at the cost of increasing reliance on RAD52-mediated HDR, which may fuel genome instability. However, our findings suggest that when challenged by DSBs, BRCA1- and 53BP1-deficient cells may become hypersensitive to, and be eliminated by, RAD52 inhibition.

MeSH Terms
Cell Cycle Checkpoints Cell Line, Tumor Cell Survival Chromatin/metabolism DNA Breaks, Double-Stranded DNA Repair Humans Protein Transport Rad51 Recombinase/metabolism Rad52 DNA Repair and Recombination Protein/metabolism Tumor Suppressor p53-Binding Protein 1/physiology
Chemicals
Chromatin RAD52 protein, human Rad52 DNA Repair and Recombination Protein TP53BP1 protein, human Tumor Suppressor p53-Binding Protein 1 RAD51 protein, human Rad51 Recombinase
Authors & Affiliations
6 authors, click to expand affiliations / ORCID
Ochs Fena
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Somyajit Kumar
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Altmeyer Matthias
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Rask Maj-Britt
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Lukas Jiri
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
Lukas Claudia
Novo Nordisk Foundation Center for Protein Research, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
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Article Info
Journal
Nature structural & molecular biology
Abbr.
Nat Struct Mol Biol
ISSN
1545-9985
DOI
10.1038/nsmb.3251
Published
2016-00-00
Epub
2016-00-27
Pages
714-21
Language
English
Region
United States
NLM ID
101186374
Subset
IM
Corrections
CommentIn
PMID: 27689875
External Links
PubMed source DOI: 10.1038/nsmb.3251 View journal details
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