DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage.
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.
Mesh Terms:
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
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
Science
Date: Aug. 14, 2015
PubMed ID: 26273056
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