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Science 339 (6120): 711-715

Copyright © 2013 by the American Association for the Advancement of Science

Rif1 Prevents Resection of DNA Breaks and Promotes Immunoglobulin Class Switching

Michela Di Virgilio,1 Elsa Callen,3,* Arito Yamane,4,* Wenzhu Zhang,5,* Mila Jankovic,1 Alexander D. Gitlin,1 Niklas Feldhahn,1 Wolfgang Resch,4 Thiago Y. Oliveira,1,6,7 Brian T. Chait,5 André Nussenzweig,3 Rafael Casellas,4 Davide F. Robbiani,1 Michel C. Nussenzweig1,2,{dagger}

Abstract: DNA double-strand breaks (DSBs) represent a threat to the genome because they can lead to the loss of genetic information and chromosome rearrangements. The DNA repair protein p53 binding protein 1 (53BP1) protects the genome by limiting nucleolytic processing of DSBs by a mechanism that requires its phosphorylation, but whether 53BP1 does so directly is not known. Here, we identify Rap1-interacting factor 1 (Rif1) as an ATM (ataxia-telangiectasia mutated) phosphorylation-dependent interactor of 53BP1 and show that absence of Rif1 results in 5'-3' DNA-end resection in mice. Consistent with enhanced DNA resection, Rif1 deficiency impairs DNA repair in the G1 and S phases of the cell cycle, interferes with class switch recombination in B lymphocytes, and leads to accumulation of chromosome DSBs.

1 Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065, USA.
2 Howard Hughes Medical Institute (HHMI), The Rockefeller University, New York, NY 10065, USA.
3 Laboratory of Genome Integrity and Center for Cancer Research, National Cancer Institute (NCI), National Institutes of Health (NIH), Bethesda, MD 20892, USA.
4 Genomics and Immunity and National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), NCI, NIH, Bethesda, MD 20892, USA.
5 Laboratory of Mass Spectrometry and Gaseous Ion Chemistry, The Rockefeller University, New York, NY 10065, USA.
6 Department of Genetics, Faculty of Medicine, University of São Paulo, Ribeirão Preto, Brazil.
7 National Institute of Science and Technology for Stem Cells and Cell Therapy, Ribeirão Preto, Brazil.

* These authors contributed equally to this work.

{dagger} To whom correspondence should be addressed. E-mail: nussen{at}rockefeller.edu


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