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PMID: 23333305 Published · ppublish English Journal Article Research Support, Non-U.S. Gov't

RIF1 is essential for 53BP1-dependent nonhomologous end joining and suppression of DNA double-strand break resection.

Molecular cell ·Vol. 49 ·No. 5 ·2013-03-07 ·Pages 858-71

Chapman JR, Barral P, Vannier JB, Borel V, Steger M, Tomas-Loba A, Sartori AA, Adams IR, Batista FD, Boulton SJ

Abstract

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.

MeSH Terms
Animals Chromosomal Proteins, Non-Histone/genetics,metabolism DNA/metabolism DNA Breaks, Double-Stranded DNA End-Joining Repair DNA-Binding Proteins/genetics,metabolism HeLa Cells Humans Mice Recombination, Genetic Telomere/metabolism Telomere-Binding Proteins/genetics,metabolism Transfection Tumor Suppressor p53-Binding Protein 1
Chemicals
Chromosomal Proteins, Non-Histone DNA-Binding Proteins Rif1 protein, mouse Telomere-Binding Proteins Trp53bp1 protein, mouse Tumor Suppressor p53-Binding Protein 1 DNA
Authors & Affiliations
10 authors, click to expand affiliations / ORCID
Chapman J Ross
DNA Damage Response Laboratory, London Research Institute, Cancer Research UK, Clare Hall, South Mimms, London, UK.
Barral Patricia
Vannier Jean-Baptiste
Borel Valérie
Steger Martin
Tomas-Loba Antonia
Sartori Alessandro A
Adams Ian R
Batista Facundo D
Boulton Simon J
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Article Info
Journal
Molecular cell
Abbr.
Mol Cell
ISSN
1097-4164
DOI
10.1016/j.molcel.2013.01.002
Published
2013-03-07
Epub
2013-00-17
Pages
858-71
Language
English
Region
United States
NLM ID
9802571
PMCID
PMC3594748
Subset
IM
Grants
Wellcome Trust · United Kingdom
Medical Research Council · MC_PC_U127580973 · United Kingdom
Cancer Research UK · United Kingdom
Corrections
CommentIn
PMID: 23473603
ErratumIn
PMID: 34214445
External Links
PubMed source DOI: 10.1016/j.molcel.2013.01.002 PMC Full Text View journal details
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