Reference: Mayle R, et al. (2015) DNA REPAIR. Mus81 and converging forks limit the mutagenicity of replication fork breakage. Science 349(6249):742-7

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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.

Reference Type
Journal Article | Research Support, N.I.H., Extramural
Authors
Mayle R, Campbell IM, Beck CR, Yu Y, Wilson M, Shaw CA, Bjergbaek L, Lupski JR, Ira G
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