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

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 Pol?, 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.

SUBMITTER: Mayle R

PROVIDER: S-EPMC4782627 | biostudies-literature | 2015 Aug

REPOSITORIES: biostudies-literature

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

Mayle Ryan R Campbell Ian M IM Beck Christine R CR Yu Yang Y Wilson Marenda M Shaw Chad A CA Bjergbaek Lotte L Lupski James R JR Ira Grzegorz G

Science (New York, N.Y.) 20150801 6249

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 end ...[more]

PMID: 26273056

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