HR Intermediates Can Induce Chromosomal Translocations

Homologous recombination (HR) generally results in accurate repair of DNA double-strand breaks (DSB), but deregulated HR can result in chromosomal rearrangements and toxic intermediates. During HR, a Rad51-coated single-stranded DNA (ssDNA) filament flanking the DSB site searches for homologous sequences by sampling double-stranded DNA (dsDNA). One filament can form heteroduplex DNA with multiple donors simultaneously if homology occurs on different molecules, creating multi-invasion (MI) intermediates. Piazza and colleagues investigated the effect of these MI intermediates on genomic stability. A single ssDNA molecule was sufficient to form an MI in combination with Rad51 and Rad54 and to tether two intact dsDNA molecules in vitro. In yeast, a genetic translocation assay showed that a DSB can induce a translocation between two donor loci that do not share homology by an HR-dependent mechanism. A single ssDNA molecule at a DSB was sufficient to induce a translocation between two intact chromosomes with homology to the invading ssDNA, but required concomitant invasions of the two donor chromosomes in a multi-invasion–induced rearrangement (MIR). This process can lead to insertions at the translocation junction that originate from the invading ssDNA. The structure-selective endonucleases Mus81-Mms4, Yen1, and Six1-Six4 were involved in MIR, whereas the 3′-flap nuclease Rad1-Rad10 and enzymes that disrupt recombination intermediates (Sgs1-Top3-Rmi1, Srs2, and Mph1) inhibited MIR. Further, MIR induced DSBs on the donors, causing frequent additional rearrangements. Altogether, these findings provide a mechanism by which MI intermediates in HR can induce chromosomal rearrangements between intact chromosomes and facilitate secondary DSBs, and suggest a potential mechanism by which chromothripsis may occur.

Piazza A, Wright WD, Heyer WD. Multi-invasions are recombination byproducts that induce chromosomal rearrangements. Cell 2017 Jul 26 [Epub ahead of print].

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