53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions

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Item Type:	Article
Title:	53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions
Creators Name:	Callen, E., Di Virgilio, M., Kruhlak, M.J., Nieto-Soler, M., Wong, N., Chen, H.T., Faryabi, R.B., Polato, F., Santos, M., Starnes, L.M., Wesemann, D.R., Lee, J.E., Tubbs, A., Sleckman, B.P., Daniel, J.A., Ge, K., Alt, F.W., Fernandez-Capetillo, O., Nussenzweig, M.C. and Nussenzweig, A.
Abstract:	The DNA damage response (DDR) protein 53BP1 protects DNA ends from excessive resection in G1, and thereby favors repair by nonhomologous end-joining (NHEJ) as opposed to homologous recombination (HR). During S phase, BRCA1 antagonizes 53BP1 to promote HR. The pro-NHEJ and antirecombinase functions of 53BP1 are mediated in part by RIF1, the only known factor that requires 53BP1 phosphorylation for its recruitment to double-strand breaks (DSBs). Here, we show that a 53BP1 phosphomutant, 53BP18A, comprising alanine substitutions of the eight most N-terminal S/TQ phosphorylation sites, mimics 53BP1 deficiency by restoring genome stability in BRCA1-deficient cells yet behaves like wild-type 53BP1 with respect to immunoglobulin class switch recombination (CSR). 53BP18A recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP18A. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.
Keywords:	B-Lymphocytes, BRCA1 Protein, Carrier Proteins, DNA End-Joining Repair, DNA-Binding Proteins, Double-Stranded DNA Breaks, Fibroblasts, Genomic Instability, Immunoglobulin Class Switching, Mammalian Embryo, Mutation, Non-Histone Chromosomal Proteins, Nuclear Proteins, Telomere-Binding Proteins, Animals, Mice
Source:	Cell
ISSN:	0092-8674
Publisher:	Cell Press
Volume:	153
Number:	6
Page Range:	1266-1280
Date:	6 June 2013
Official Publication:	https://doi.org/10.1016/j.cell.2013.05.023
PubMed:	View item in PubMed

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