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A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination

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 an...

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Autores principales: León-Ortiz, Ana María, Panier, Stephanie, Sarek, Grzegorz, Vannier, Jean-Baptiste, Patel, Harshil, Campbell, Peter J., Boulton, Simon J.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783719/
https://www.ncbi.nlm.nih.gov/pubmed/29351848
http://dx.doi.org/10.1016/j.molcel.2017.12.014
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author León-Ortiz, Ana María
Panier, Stephanie
Sarek, Grzegorz
Vannier, Jean-Baptiste
Patel, Harshil
Campbell, Peter J.
Boulton, Simon J.
author_facet León-Ortiz, Ana María
Panier, Stephanie
Sarek, Grzegorz
Vannier, Jean-Baptiste
Patel, Harshil
Campbell, Peter J.
Boulton, Simon J.
author_sort León-Ortiz, Ana María
collection PubMed
description 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.
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spelling pubmed-57837192018-01-29 A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination León-Ortiz, Ana María Panier, Stephanie Sarek, Grzegorz Vannier, Jean-Baptiste Patel, Harshil Campbell, Peter J. Boulton, Simon J. Mol Cell Article 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. Cell Press 2018-01-18 /pmc/articles/PMC5783719/ /pubmed/29351848 http://dx.doi.org/10.1016/j.molcel.2017.12.014 Text en © 2017 The Author(s) http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
León-Ortiz, Ana María
Panier, Stephanie
Sarek, Grzegorz
Vannier, Jean-Baptiste
Patel, Harshil
Campbell, Peter J.
Boulton, Simon J.
A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination
title A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination
title_full A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination
title_fullStr A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination
title_full_unstemmed A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination
title_short A Distinct Class of Genome Rearrangements Driven by Heterologous Recombination
title_sort distinct class of genome rearrangements driven by heterologous recombination
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5783719/
https://www.ncbi.nlm.nih.gov/pubmed/29351848
http://dx.doi.org/10.1016/j.molcel.2017.12.014
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