RIF1 Is Essential for 53BP1-Dependent Nonhomologous End Joining and Suppression of DNA Double-Strand Break Resection
pmid: 23333305
pmc: PMC3594748
RIF1 Is Essential for 53BP1-Dependent Nonhomologous End Joining and Suppression of DNA Double-Strand Break Resection
The appropriate execution of DNA double-strand break (DSB) repair is critical for genome stability and tumor avoidance. 53BP1 and BRCA1 directly influence DSB repair pathway choice by regulating 5' end resection, but how this is achieved remains uncertain. Here we report that Rif1(-/-) mice are severely compromised for 53BP1-dependent class switch recombination (CSR) and fusion of dysfunctional telomeres. The inappropriate accumulation of RIF1 at DSBs in S phase is antagonized by BRCA1, and deletion of Rif1 suppresses toxic nonhomologous end joining (NHEJ) induced by PARP inhibition in Brca1-deficient cells. Mechanistically, RIF1 is recruited to DSBs via the N-terminal phospho-SQ/TQ domain of 53BP1, and DSBs generated by ionizing radiation or during CSR are hyperresected in the absence of RIF1. Thus, RIF1 and 53BP1 cooperate to block DSB resection to promote NHEJ in G1, which is antagonized by BRCA1 in S phase to ensure a switch of DSB repair mode to homologous recombination.
- NHS Lothian United Kingdom
- Institute of Molecular Cancer Research Switzerland
- Medical Research Council United Kingdom
- Imperial College Healthcare NHS Trust United Kingdom
- UNIVERSITAET ZUERICH Switzerland
Recombination, Genetic, 570, DNA End-Joining Repair, Chromosomal Proteins, Non-Histone, 10061 Institute of Molecular Cancer Research, Telomere-Binding Proteins, 610, Correction, Cell Biology, DNA, Telomere, Transfection, Article, 1307 Cell Biology, DNA-Binding Proteins, Mice, 1312 Molecular Biology, 570 Life sciences; biology, Animals, Humans, DNA Breaks, Double-Stranded, Tumor Suppressor p53-Binding Protein 1, Molecular Biology, HeLa Cells
Recombination, Genetic, 570, DNA End-Joining Repair, Chromosomal Proteins, Non-Histone, 10061 Institute of Molecular Cancer Research, Telomere-Binding Proteins, 610, Correction, Cell Biology, DNA, Telomere, Transfection, Article, 1307 Cell Biology, DNA-Binding Proteins, Mice, 1312 Molecular Biology, 570 Life sciences; biology, Animals, Humans, DNA Breaks, Double-Stranded, Tumor Suppressor p53-Binding Protein 1, Molecular Biology, HeLa Cells
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