MOF phosphorylation by ATM regulates 53BP1-mediated double-strand break repair pathway choice

Cell Rep. 2014 Jul 10;8(1):177-89. doi: 10.1016/j.celrep.2014.05.044. Epub 2014 Jun 19.

Abstract

Cell-cycle phase is a critical determinant of the choice between DNA damage repair by nonhomologous end-joining (NHEJ) or homologous recombination (HR). Here, we report that double-strand breaks (DSBs) induce ATM-dependent MOF (a histone H4 acetyl-transferase) phosphorylation (p-T392-MOF) and that phosphorylated MOF colocalizes with γ-H2AX, ATM, and 53BP1 foci. Mutation of the phosphorylation site (MOF-T392A) impedes DNA repair in S and G2 phase but not G1 phase cells. Expression of MOF-T392A also blocks the reduction in DSB-associated 53BP1 seen in wild-type S/G2 phase cells, resulting in enhanced 53BP1 and reduced BRCA1 association. Decreased BRCA1 levels at DSB sites correlates with defective repairosome formation, reduced HR repair, and decreased cell survival following irradiation. These data support a model whereby ATM-mediated MOF-T392 phosphorylation modulates 53BP1 function to facilitate the subsequent recruitment of HR repair proteins, uncovering a regulatory role for MOF in DSB repair pathway choice during S/G2 phase.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Ataxia Telangiectasia Mutated Proteins / genetics
  • Ataxia Telangiectasia Mutated Proteins / metabolism*
  • BRCA1 Protein / genetics
  • BRCA1 Protein / metabolism
  • Cell Line, Tumor
  • DNA Breaks, Double-Stranded
  • G1 Phase Cell Cycle Checkpoints
  • G2 Phase Cell Cycle Checkpoints
  • HEK293 Cells
  • Histone Acetyltransferases / genetics
  • Histone Acetyltransferases / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / genetics
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Mice
  • Mutation
  • Phosphorylation
  • Recombinational DNA Repair*
  • Tumor Suppressor p53-Binding Protein 1

Substances

  • BRCA1 Protein
  • Intracellular Signaling Peptides and Proteins
  • TP53BP1 protein, human
  • Tumor Suppressor p53-Binding Protein 1
  • Histone Acetyltransferases
  • KAT8 protein, human
  • Ataxia Telangiectasia Mutated Proteins