Mus81 and converging forks limit the mutagenicity of replication fork breakage

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Science  14 Aug 2015:
Vol. 349, Issue 6249, pp. 742-747
DOI: 10.1126/science.aaa8391

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How to repair broken replication forks

Double-strand breaks in DNA are extremely dangerous to the integrity of our genomes. Most arise from problems encountered by replication forks during duplication of genomic DNA. Break-induced replication is known to use an error-prone DNA polymerase to repair such damage. Mayle et al. show that cells limit error-prone DNA synthesis by preventing the DNA polymerase from inadvertently switching to a related sequence with an incorrect template. The repair of the break is achieved by using a structure-specific nuclease to prevent formation of a long single-stranded region.

Science, this issue p. 742


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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