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

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  • Ryan Mayle, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  • ,
  • Ian M Campbell, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, Danmark
  • Christine R Beck, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, Danmark
  • Yang Yu, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA
  • ,
  • Marenda Wilson, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, Danmark
  • Chad A Shaw, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, Danmark
  • Lotte Bjergbaek
  • James R Lupski, Department of Molecular and Human Genetics, Baylor College of Medicine & Department of Pediatrics, Baylor College of Medicine & Texas Children’s Hospital, Houston, TX, USA, Texas Children's Hospital, Baylor College of Medicine, Division of Pediatris Surgery
  • ,
  • Grzegorz Ira, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, Danmark

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.

OriginalsprogEngelsk
TidsskriftScience
Vol/bind349
Nummer6249
Sider (fra-til)742-747
Antal sider6
ISSN0036-8075
DOI
StatusUdgivet - 14 aug. 2015

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