Aarhus University Seal / Aarhus Universitets segl

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

DOI

  • 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, Denmark
  • Christine R Beck, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, Denmark
  • 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, Denmark
  • Chad A Shaw, Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA, Denmark
  • 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, Denmark

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.

Original languageEnglish
JournalScience
Volume349
Issue6249
Pages (from-to)742-747
Number of pages6
ISSN0036-8075
DOIs
Publication statusPublished - 14 Aug 2015

    Research areas

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

See relations at Aarhus University Citationformats

ID: 95387539