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PMID: 20362325 Published · ppublish English Journal Article Research Support, N.I.H., Extramural Research Support, N.I.H., Intramural Research Support, Non-U.S. Gov't Comment

53BP1 inhibits homologous recombination in Brca1-deficient cells by blocking resection of DNA breaks.

Cell ·Vol. 141 ·No. 2 ·2010-04-16 ·Pages 243-54

Bunting SF, Callén E, Wong N, Chen HT, Polato F, Gunn A, Bothmer A, Feldhahn N, Fernandez-Capetillo O, Cao L, Xu X, Deng CX, Finkel T, Nussenzweig M, Stark JM, Nussenzweig A

Abstract

Defective DNA repair by homologous recombination (HR) is thought to be a major contributor to tumorigenesis in individuals carrying Brca1 mutations. Here, we show that DNA breaks in Brca1-deficient cells are aberrantly joined into complex chromosome rearrangements by a process dependent on the nonhomologous end-joining (NHEJ) factors 53BP1 and DNA ligase 4. Loss of 53BP1 alleviates hypersensitivity of Brca1 mutant cells to PARP inhibition and restores error-free repair by HR. Mechanistically, 53BP1 deletion promotes ATM-dependent processing of broken DNA ends to produce recombinogenic single-stranded DNA competent for HR. In contrast, Lig4 deficiency does not rescue the HR defect in Brca1 mutant cells but prevents the joining of chromatid breaks into chromosome rearrangements. Our results illustrate that HR and NHEJ compete to process DNA breaks that arise during DNA replication and that shifting the balance between these pathways can be exploited to selectively protect or kill cells harboring Brca1 mutations.

MeSH Terms
Animals B-Lymphocytes/metabolism BRCA1 Protein/genetics Chromosomal Proteins, Non-Histone DNA Breaks DNA Repair DNA-Binding Proteins Female Genomic Instability Humans Intracellular Signaling Peptides and Proteins/metabolism Mice Tumor Suppressor p53-Binding Protein 1
Chemicals
BRCA1 Protein Chromosomal Proteins, Non-Histone DNA-Binding Proteins Intracellular Signaling Peptides and Proteins Trp53bp1 protein, mouse Tumor Suppressor p53-Binding Protein 1
Authors & Affiliations
16 authors, click to expand affiliations / ORCID
Bunting Samuel F
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Callén Elsa
Wong Nancy
Chen Hua-Tang
Polato Federica
Gunn Amanda
Bothmer Anne
Feldhahn Niklas
Fernandez-Capetillo Oscar
Cao Liu
Xu Xiaoling
Deng Chu-Xia
Finkel Toren
Nussenzweig Michel
Stark Jeremy M
Nussenzweig André
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Article Info
Journal
Cell
Abbr.
Cell
ISSN
1097-4172
DOI
10.1016/j.cell.2010.03.012
Published
2010-04-16
Epub
2010-00-01
Pages
243-54
Language
English
Region
United States
NLM ID
0413066
PMCID
PMC2857570
Subset
IM
Grants
NIAID NIH HHS · R01 AI037526 · United States
NCI NIH HHS · R01 CA120954-04 · United States
Intramural NIH HHS · Z01 BC010283-10 · United States
NCI NIH HHS · R01 CA120954 · United States
Howard Hughes Medical Institute · United States
Intramural NIH HHS · Z99 CA999999 · United States
Intramural NIH HHS · Z01 BC010959-01 · United States
NCI NIH HHS · R01CA120954 · United States
NIAID NIH HHS · AI037526 · United States
NIAID NIH HHS · R37 AI037526 · United States
Corrections
CommentOn
PMID: 20478525
External Links
PubMed source DOI: 10.1016/j.cell.2010.03.012 PMC Full Text View journal details
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