Details

Autor(en) / Beteiligte

• León-Ortiz, Ana María
• Panier, Stephanie
• Sarek, Grzegorz
• Vannier, Jean-Baptiste
• Patel, Harshil
• Campbell, Peter J.
• Boulton, Simon J.

Titel

A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination

Ist Teil von

• Molecular cell, 2018-01, Vol.69 (2), p.292-305.e6

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2018

Quelle

Elsevier ScienceDirect Journals

Beschreibungen/Notizen

• 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. [Display omitted] •Heterologous recombination (Ht-REC) can occur between non-identical sequences•RTEL1, HIM-6/BLM, and BRC-1/BRCA1 prevent Ht-REC•MSH-2/MSH-6 drives Ht-REC in the absence of RTEL-1 or BRC-1•Lack of mammalian RTEL1 causes complex genome rearrangements consistent with Ht-REC León-Ortiz et al. demonstrate that recombination is possible between non-identical sequences (Ht-REC) but is blocked by RTEL-1, HIM-6/BLM, and BRC-1/BRCA1 in C. elegans. MSH-2/MSH-6 instead drives Ht-REC in the absence of RTEL-1 or BRC-1. Ht-REC likely contributes to complex genome rearrangements in the absence of mammalian RTEL1 and in cancer.