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 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.
Bunting
Samuel F
SF
Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Callén
Elsa
E
Wong
Nancy
N
Chen
Hua-Tang
HT
Polato
Federica
F
Gunn
Amanda
A
Bothmer
Anne
A
Feldhahn
Niklas
N
Fernandez-Capetillo
Oscar
O
Cao
Liu
L
Xu
Xiaoling
X
Deng
Chu-Xia
CX
Finkel
Toren
T
Nussenzweig
Michel
M
Stark
Jeremy M
JM
Nussenzweig
André
A
D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D019313:BRCA1 Protein / Q000235:genetics*; D002868:Chromosomal Proteins, Non-Histone; D053960:DNA Breaks; D004260:DNA Repair; D004268:DNA-Binding Proteins; D005260:Female; D042822:Genomic Instability; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D051379:Mice; D000071857:Tumor Suppressor p53-Binding Protein 1
D019313:BRCA1 Protein; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1