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.
Original language | English |
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Journal | Science |
Volume | 349 |
Issue | 6249 |
Pages (from-to) | 742-747 |
Number of pages | 6 |
ISSN | 0036-8075 |
DOIs | |
Publication status | Published - 14 Aug 2015 |
Keywords
- Alu 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