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

Ryan Mayle, Ian M Campbell, Christine R Beck, Yang Yu, Marenda Wilson, Chad A Shaw, Lotte Bjergbaek, James R Lupski, Grzegorz Ira

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

    153 Citations (Scopus)

    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.

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

    Keywords

    • 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

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