title: 53BP1 mediates productive and mutagenic DNA repair through distinct phosphoprotein interactions.
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.
authors.affiliation: Laboratory of Genome Integrity, National Cancer Institute, NIH, Bethesda, MD 20892, USA.
authors.forename: Elsa
authors.initials: E
authors.lastname: Callen
authors.forename: Michela
authors.initials: M
authors.lastname: Di Virgilio
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Kruhlak
authors.forename: Maria
authors.initials: M
authors.lastname: Nieto-Soler
authors.forename: Nancy
authors.initials: N
authors.lastname: Wong
authors.forename: Hua-Tang
authors.initials: HT
authors.lastname: Chen
authors.forename: Robert B
authors.initials: RB
authors.lastname: Faryabi
authors.forename: Federica
authors.initials: F
authors.lastname: Polato
authors.forename: Margarida
authors.initials: M
authors.lastname: Santos
authors.forename: Linda M
authors.initials: LM
authors.lastname: Starnes
authors.forename: Duane R
authors.initials: DR
authors.lastname: Wesemann
authors.forename: Ji-Eun
authors.initials: JE
authors.lastname: Lee
authors.forename: Anthony
authors.initials: A
authors.lastname: Tubbs
authors.forename: Barry P
authors.initials: BP
authors.lastname: Sleckman
authors.forename: Jeremy A
authors.initials: JA
authors.lastname: Daniel
authors.forename: Kai
authors.initials: K
authors.lastname: Ge
authors.forename: Frederick W
authors.initials: FW
authors.lastname: Alt
authors.forename: Oscar
authors.initials: O
authors.lastname: Fernandez-Capetillo
authors.forename: Michel C
authors.initials: MC
authors.lastname: Nussenzweig
authors.forename: André
authors.initials: A
authors.lastname: Nussenzweig
mesh_terms: D000818:Animals; D001402:B-Lymphocytes / Q000378:metabolism; D019313:BRCA1 Protein / Q000378:metabolism; D002352:Carrier Proteins / Q000378:metabolism*; D002868:Chromosomal Proteins, Non-Histone / Q000235:genetics / Q000378:metabolism*; D053903:DNA Breaks, Double-Stranded; D059766:DNA End-Joining Repair; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian / Q000166:cytology / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D042822:Genomic Instability; D017578:Immunoglobulin Class Switching; D051379:Mice; D009154:Mutation; D009687:Nuclear Proteins / Q000378:metabolism*; D034501:Telomere-Binding Proteins / Q000378:metabolism*; D000071857:Tumor Suppressor p53-Binding Protein 1
chemical_list: D019313:BRCA1 Protein; D002352:Carrier Proteins; D002868:Chromosomal Proteins, Non-Histone; D004268:DNA-Binding Proteins; D009687:Nuclear Proteins; C412792:Paxip1 protein, mouse; C492748:Rif1 protein, mouse; D034501:Telomere-Binding Proteins; C498302:Trp53bp1 protein, mouse; D000071857:Tumor Suppressor p53-Binding Protein 1