53BP1 Inhibits Homologous Recombination in Brca1-Deficient Cells by Blocking Resection of DNA Breaks

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 nonho...

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Bibliographic Details
Published in:Cell 2010-04, Vol.141 (2), p.243-254
Main Authors: Bunting, Samuel F., 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
Format: Article
Language:English
Subjects:
Animals
B-Lymphocytes - metabolism
BRCA1 Protein - genetics
Chromosomal Proteins, Non-Histone
DNA
DNA Breaks
DNA Repair
DNA-Binding Proteins
Female
Genomic Instability
Humans
HUMDISEASE
Intracellular Signaling Peptides and Proteins - metabolism
Mice
Tumor Suppressor p53-Binding Protein 1
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Summary: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. [Display omitted] ► 53BP1 and Brca1 regulate the choice between HR and NHEJ pathways for DNA repair ► 53BP1 deletion promotes HR by increasing ATM-dependent resection of DNA breaks ► 53BP1 mutation protects Brca1-deficient cells from death induced by PARP inhibition ► Lig4 joins unrepaired DNA breaks into radial chromosomes in Brca1 mutant cells
ISSN:0092-8674
1097-4172
DOI:10.1016/j.cell.2010.03.012