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...

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Published inScience (American Association for the Advancement of Science) Vol. 349; no. 6249; pp. 742 - 747
Main Authors Mayle, Ryan, Campbell, Ian M., Beck, Christine R., Yu, Yang, Wilson, Marenda, Shaw, Chad A., Bjergbaek, Lotte, Lupski, James R., Ira, Grzegorz
Format Journal Article
LanguageEnglish
Published American Association for the Advancement of Science 14.08.2015
Subjects
Breakage
Breaking
Deoxyribonucleic acid
DNA polymerase
Genomes
Repair
Replication
Synthesis
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ISSN0036-8075
1095-9203
DOI10.1126/science.aaa8391

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Summary: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.
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Present address: Graduate School of Biomedical Sciences at Houston, University of Texas, 6767 Bertner Avenue, Houston, TX 77030, USA.
ISSN:0036-8075
1095-9203
DOI:10.1126/science.aaa8391