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

Research output: Contribution to journalJournal articleResearchpeer-review

  • E. Callen
  • N. Wong
  • H.-T. Chen
  • R.B. Faryabi
  • F. Polato
  • Margarida Santos
  • A. Nussenzweig
  • M.J. Kruhlak
  • M. Di Virgilio
  • M.C. Nussenzweig
  • M. Nieto-Soler
  • O. Fernandez-Capetillo
  • L.M. Starnes
  • J.A. Daniel
  • D.R. Wesemann
  • F.W. Alt
  • J.-E. Lee
  • K. Ge
  • A. Tubbs
  • B.P. Sleckman
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, 53BP1, 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). 53BP1 recruits RIF1 but fails to recruit the DDR protein PTIP to DSBs, and disruption of PTIP phenocopies 53BP1. We conclude that 53BP1 promotes productive CSR and suppresses mutagenic DNA repair through distinct phosphodependent interactions with RIF1 and PTIP.
Original languageEnglish
JournalCell
Volume153
Issue number6
Pages (from-to)1266-1280
Number of pages15
ISSN0092-8674
DOIs
Publication statusPublished - 6 Jun 2013

ID: 46439919