A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination

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

doi:10.1016/j.molcel.2017.12.014

Ana María León-Ortiz, Stephanie Panier + Show 5 more

Open Access

https://doi.org/10.1016/j.molcel.2017.12.014

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Abstract

SummaryErroneous 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.

Highlights

Genome instability is the driving force that causes mutations and chromosome rearrangements, which lead to the development of cancers
Using a reporter system in Caenorhabditis elegans to detect heterologous recombination (Ht-REC), we demonstrate that recombination between heterologous sequences is extremely rare in wild-type animals but does occur with high frequency in mutants defective for C. elegans RTEL1, BRCA1, and BLM (RTEL-1, BRC-1, and HIM-6, respectively)
Because the RTEL1 helicase disassembles displacement loop (D-loop), we reasoned that it could act to ensure the quality of meiotic recombination by dismantling erroneous strand-pairing events arising from the invasion of a broken DNA end into a donor sequence with limited homology, such as within the context of a balanced region

Summary

Introduction

Genome instability is the driving force that causes mutations and chromosome rearrangements, which lead to the development of cancers. Chromosomal translocations that result in gene fusions have been recognized for many decades as drivers of tumor development Many of these rearrangements occur between sequences that share no homology and are believed to occur via non-homologous end joining (NHEJ), in which chromosomal breaks from different parts of the genome are joined together by simple ligation (Bunting and Nussenzweig, 2013). Instead, the second end of the break is captured by the D-loop, this can lead to the formation of a double Holliday junction (dHJ), which is either dissolved to produce exclusively NCO events or resolved to produce both crossovers (COs) and NCOs. dissolution is achieved by the BTR complex, composed of the BLM helicase, the TOP3 topoisomerase, and an RMI scaffold (RMI1 and 2) (Mankouri and Hickson, 2007; Wu and Hickson, 2003; Xu et al, 2008), resolution involves the action of several different structure-specific endonucleases that can cleave the junctions to result in either CO or NCO products (for reviews, see Jasin and Rothstein, 2013; West et al, 2015)

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