DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage

Science. 2015 Aug 14;349(6249):742-7. doi: 10.1126/science.aaa8391.

Abstract

Most spontaneous DNA double-strand breaks (DSBs) result from replication-fork breakage. Break-induced replication (BIR), a genome rearrangement-prone repair mechanism that requires the Pol32/POLD3 subunit of eukaryotic DNA Polδ, was proposed to repair broken forks, but how genome destabilization is avoided was unknown. We show that broken fork repair initially uses error-prone Pol32-dependent synthesis, but that mutagenic synthesis is limited to within a few kilobases from the break by Mus81 endonuclease and a converging fork. Mus81 suppresses template switches between both homologous sequences and diverged human Alu repetitive elements, highlighting its importance for stability of highly repetitive genomes. We propose that lack of a timely converging fork or Mus81 may propel genome instability observed in cancer.

Publication types

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

MeSH terms

  • Alu Elements
  • Base Sequence
  • DNA Breaks, Double-Stranded*
  • DNA Repair / genetics*
  • DNA Replication / genetics*
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism*
  • DNA-Directed DNA Polymerase / metabolism
  • Endonucleases / genetics
  • Endonucleases / metabolism*
  • Genomic Instability*
  • Humans
  • Molecular Sequence Data
  • Neoplasms / genetics
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*

Substances

  • DNA-Binding Proteins
  • Pol32 protein, S cerevisiae
  • Saccharomyces cerevisiae Proteins
  • DNA-Directed DNA Polymerase
  • Endonucleases
  • MUS81 protein, S cerevisiae