A distinct class of genome rearrangements driven by heterologous recombination
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Ana María León-Ortiz Stephanie Panier Grzegorz Sarek Jean-Baptiste Vannier Harshil Patel Peter J Campbell Simon BoultonAbstract
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.
Journal details
Journal Molecular Cell
Volume 69
Issue number 2
Pages 292-305.e6
Available online
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Publisher website (DOI) 10.1016/j.molcel.2017.12.014
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Europe PubMed Central 29351848
Pubmed 29351848
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