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Title

Complex Chromosomal Rearrangements Mediated by Break-Induced Replication Involve Structure-Selective Endonucleases

AuthorsPardo, Benjamín ; Aguilera, Andrés
Issue Date27-Sep-2012
PublisherPublic Library of Science
CitationPLoS Genetics 8(9): e1002979 (2012)
AbstractDNA double-strand break (DSB) repair occurring in repeated DNA sequences often leads to the generation of chromosomal rearrangements. Homologous recombination normally ensures a faithful repair of DSBs through a mechanism that transfers the genetic information of an intact donor template to the broken molecule. When only one DSB end shares homology to the donor template, conventional gene conversion fails to occur and repair can be channeled to a recombinationdependent replication pathway termed break-induced replication (BIR), which is prone to produce chromosome nonreciprocal translocations (NRTs), a classical feature of numerous human cancers. Using a newly designed substrate for the analysis of DSB–induced chromosomal translocations, we show that Mus81 and Yen1 structure-selective endonucleases (SSEs) promote BIR, thus causing NRTs. We propose that Mus81 and Yen1 are recruited at the strand invasion intermediate to allow the establishment of a replication fork, which is required to complete BIR. Replication template switching during BIR, a feature of this pathway, engenders complex chromosomal rearrangements when using repeated DNA sequences dispersed over the genome. We demonstrate here that Mus81 and Yen1, together with Slx4, also promote template switching during BIR. Altogether, our study provides evidence for a role of SSEs at multiple steps during BIR, thus participating in the destabilization of the genome by generating complex chromosomal rearrangements.
DescriptionThis is an open-access article distributed under the terms of the Creative Commons Attribution License.
Publisher version (URL)http://dx.doi.org/10.1371/journal.pgen.1002979
URIhttp://hdl.handle.net/10261/121576
DOI10.1371/journal.pgen.1002979
ISSN1553-7390
E-ISSN1553-7404
Appears in Collections:(CABIMER) Artículos
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