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A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination.

Molecular cell | 2018

Erroneous DNA repair by heterologous recombination (Ht-REC) is a potential threat to genome stability, but evidence supporting its prevalence is lacking. Here we demonstrate that recombination is possible between heterologous sequences and that it is a source of chromosomal alterations in mitotic and meiotic cells. Mechanistically, we find that the RTEL1 and HIM-6/BLM helicases and the BRCA1 homolog BRC-1 counteract Ht-REC in Caenorhabditis elegans, whereas mismatch repair does not. Instead, MSH-2/6 drives Ht-REC events in rtel-1 and brc-1 mutants and excessive crossovers in rtel-1 mutant meioses. Loss of vertebrate Rtel1 also causes a variety of unusually large and complex structural variations, including chromothripsis, breakage-fusion-bridge events, and tandem duplications with distant intra-chromosomal insertions, whose structure are consistent with a role for RTEL1 in preventing Ht-REC during break-induced replication. Our data establish Ht-REC as an unappreciated source of genome instability that underpins a novel class of complex genome rearrangements that likely arise during replication stress.

Pubmed ID: 29351848 RIS Download

Associated grants

  • Agency: Medical Research Council, United Kingdom
    Id: FC0010048
  • Agency: Wellcome Trust, United Kingdom
    Id: WT088340MA
  • Agency: Cancer Research UK, United Kingdom
    Id: FC0010048
  • Agency: Wellcome Trust, United Kingdom
    Id: 077012/Z/05/Z
  • Agency: Medical Research Council, United Kingdom
    Id: MC_UP_1102/14
  • Agency: Wellcome Trust, United Kingdom
    Id: FC0010048
  • Agency: Wellcome Trust, United Kingdom

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