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

TitleDNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage.
Publication TypeJournal Article
Year of Publication2015
AuthorsMayle, R, Campbell, IM, Beck, CR, Yu, Y, Wilson, M, Shaw, CA, Bjergbaek, L, Lupski, JR, Ira, G
JournalScience
Volume349
Issue6249
Pagination742-7
Date Published2015 Aug 14
ISSN1095-9203
KeywordsAlu 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
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.

DOI10.1126/science.aaa8391
Alternate JournalScience
PubMed ID26273056
PubMed Central IDPMC4782627
Grant ListU54 HG006542 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
HG006542 / HG / NHGRI NIH HHS / United States
NS083159 / NS / NINDS NIH HHS / United States
F31 NS083159 / NS / NINDS NIH HHS / United States
R01 GM080600 / GM / NIGMS NIH HHS / United States
R01 NS058529 / NS / NINDS NIH HHS / United States
GM080600 / GM / NIGMS NIH HHS / United States
NS058529 / NS / NINDS NIH HHS / United States

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