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ATRX and RECQ5 define distinct homologous recombination subpathways

Homologous recombination (HR) is an important DNA double-strand break (DSB) repair pathway that copies sequence information lost at the break site from an undamaged homologous template. This involves the formation of a recombination structure that is processed to restore the original sequence but al...

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Autores principales: Elbakry, Amira, Juhász, Szilvia, Chan, Ki Choi, Löbrich, Markus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: National Academy of Sciences 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826375/
https://www.ncbi.nlm.nih.gov/pubmed/33431668
http://dx.doi.org/10.1073/pnas.2010370118
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author Elbakry, Amira
Juhász, Szilvia
Chan, Ki Choi
Löbrich, Markus
author_facet Elbakry, Amira
Juhász, Szilvia
Chan, Ki Choi
Löbrich, Markus
author_sort Elbakry, Amira
collection PubMed
description Homologous recombination (HR) is an important DNA double-strand break (DSB) repair pathway that copies sequence information lost at the break site from an undamaged homologous template. This involves the formation of a recombination structure that is processed to restore the original sequence but also harbors the potential for crossover (CO) formation between the participating molecules. Synthesis-dependent strand annealing (SDSA) is an HR subpathway that prevents CO formation and is thought to predominate in mammalian cells. The chromatin remodeler ATRX promotes an alternative HR subpathway that has the potential to form COs. Here, we show that ATRX-dependent HR outcompetes RECQ5-dependent SDSA for the repair of most two-ended DSBs in human cells and leads to the frequent formation of COs, assessed by measuring sister chromatid exchanges (SCEs). We provide evidence that subpathway choice is dependent on interaction of both ATRX and RECQ5 with proliferating cell nuclear antigen. We also show that the subpathway usage varies among different cancer cell lines and compare it to untransformed cells. We further observe HR intermediates arising as ionizing radiation (IR)-induced ultra-fine bridges only in cells expressing ATRX and lacking MUS81 and GEN1. Consistently, damage-induced MUS81 recruitment is only observed in ATRX-expressing cells. Cells lacking BLM show similar MUS81 recruitment and IR-induced SCE formation as control cells. Collectively, these results suggest that the ATRX pathway involves the formation of HR intermediates whose processing is entirely dependent on MUS81 and GEN1 and independent of BLM. We propose that the predominant ATRX-dependent HR subpathway forms joint molecules distinct from classical Holliday junctions.
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spelling pubmed-78263752021-01-28 ATRX and RECQ5 define distinct homologous recombination subpathways Elbakry, Amira Juhász, Szilvia Chan, Ki Choi Löbrich, Markus Proc Natl Acad Sci U S A Biological Sciences Homologous recombination (HR) is an important DNA double-strand break (DSB) repair pathway that copies sequence information lost at the break site from an undamaged homologous template. This involves the formation of a recombination structure that is processed to restore the original sequence but also harbors the potential for crossover (CO) formation between the participating molecules. Synthesis-dependent strand annealing (SDSA) is an HR subpathway that prevents CO formation and is thought to predominate in mammalian cells. The chromatin remodeler ATRX promotes an alternative HR subpathway that has the potential to form COs. Here, we show that ATRX-dependent HR outcompetes RECQ5-dependent SDSA for the repair of most two-ended DSBs in human cells and leads to the frequent formation of COs, assessed by measuring sister chromatid exchanges (SCEs). We provide evidence that subpathway choice is dependent on interaction of both ATRX and RECQ5 with proliferating cell nuclear antigen. We also show that the subpathway usage varies among different cancer cell lines and compare it to untransformed cells. We further observe HR intermediates arising as ionizing radiation (IR)-induced ultra-fine bridges only in cells expressing ATRX and lacking MUS81 and GEN1. Consistently, damage-induced MUS81 recruitment is only observed in ATRX-expressing cells. Cells lacking BLM show similar MUS81 recruitment and IR-induced SCE formation as control cells. Collectively, these results suggest that the ATRX pathway involves the formation of HR intermediates whose processing is entirely dependent on MUS81 and GEN1 and independent of BLM. We propose that the predominant ATRX-dependent HR subpathway forms joint molecules distinct from classical Holliday junctions. National Academy of Sciences 2021-01-19 2021-01-11 /pmc/articles/PMC7826375/ /pubmed/33431668 http://dx.doi.org/10.1073/pnas.2010370118 Text en Copyright © 2021 the Author(s). Published by PNAS. https://creativecommons.org/licenses/by-nc-nd/4.0/ https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND) (https://creativecommons.org/licenses/by-nc-nd/4.0/) .
spellingShingle Biological Sciences
Elbakry, Amira
Juhász, Szilvia
Chan, Ki Choi
Löbrich, Markus
ATRX and RECQ5 define distinct homologous recombination subpathways
title ATRX and RECQ5 define distinct homologous recombination subpathways
title_full ATRX and RECQ5 define distinct homologous recombination subpathways
title_fullStr ATRX and RECQ5 define distinct homologous recombination subpathways
title_full_unstemmed ATRX and RECQ5 define distinct homologous recombination subpathways
title_short ATRX and RECQ5 define distinct homologous recombination subpathways
title_sort atrx and recq5 define distinct homologous recombination subpathways
topic Biological Sciences
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7826375/
https://www.ncbi.nlm.nih.gov/pubmed/33431668
http://dx.doi.org/10.1073/pnas.2010370118
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