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53BP1 inhibits homologous recombination in brca1-deficient cells by blocking resection of DNA breaks
Bunting S.F.2; Callen E.2; Wong N.2; Chen H.-T.2; Polato F.2; Gunn A.6; Bothmer A.1; Feldhahn N.1; Fernandez-Capetillo O.3; Cao L.4; Xu X.5; Deng C.-X.5; Finkel T.4; Nussenzweig M.1; Stark J.M.6; Nussenzweig A.2
2010-04-01
Source PublicationCell
ISSN00928674
Volume141Issue:2Pages:243-254
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. © 2010 Elsevier Inc.

KeywordDna Humdisease
DOI10.1016/j.cell.2010.03.012
URLView the original
Indexed BySCI
Language英语
WOS Research AreaBiochemistry & Molecular Biology ; Cell Biology
WOS SubjectBiochemistry & Molecular Biology ; Cell Biology
WOS IDWOS:000276738400015
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Citation statistics
Cited Times [WOS]:779   [WOS Record]     [Related Records in WOS]
Document TypeJournal article
CollectionFaculty of Health Sciences
Personal research not belonging to the institution
Co-First AuthorBunting S.F.; Callen E.
Corresponding AuthorNussenzweig A.
Affiliation1.Rockefeller University
2.National Cancer Institute
3.Centro Nacional de Investigaciones Oncologicas
4.National Heart, Lung, and Blood Institute
5.National Institutes of Health, Bethesda
6.City of Hope National Med Center
Recommended Citation
GB/T 7714
Bunting S.F.,Callen E.,Wong N.,et al. 53BP1 inhibits homologous recombination in brca1-deficient cells by blocking resection of DNA breaks[J]. Cell,2010,141(2):243-254.
APA Bunting S.F..,Callen E..,Wong N..,Chen H.-T..,Polato F..,...&Nussenzweig A..(2010).53BP1 inhibits homologous recombination in brca1-deficient cells by blocking resection of DNA breaks.Cell,141(2),243-254.
MLA Bunting S.F.,et al."53BP1 inhibits homologous recombination in brca1-deficient cells by blocking resection of DNA breaks".Cell 141.2(2010):243-254.
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