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Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage

The structure-specific Mus81-Eme1/Mms4 endonuclease contributes importantly to DNA repair and genome integrity maintenance. Here, using budding yeast, we have studied its function and regulation during the cellular response to DNA damage and show that this endonuclease is necessary for successful ch...

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Autores principales: Saugar, Irene, Vázquez, María Victoria, Gallo-Fernández, María, Ortiz-Bazán, María Ángeles, Segurado, Mónica, Calzada, Arturo, Tercero, José Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Oxford University Press 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799426/
https://www.ncbi.nlm.nih.gov/pubmed/23901010
http://dx.doi.org/10.1093/nar/gkt645
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author Saugar, Irene
Vázquez, María Victoria
Gallo-Fernández, María
Ortiz-Bazán, María Ángeles
Segurado, Mónica
Calzada, Arturo
Tercero, José Antonio
author_facet Saugar, Irene
Vázquez, María Victoria
Gallo-Fernández, María
Ortiz-Bazán, María Ángeles
Segurado, Mónica
Calzada, Arturo
Tercero, José Antonio
author_sort Saugar, Irene
collection PubMed
description The structure-specific Mus81-Eme1/Mms4 endonuclease contributes importantly to DNA repair and genome integrity maintenance. Here, using budding yeast, we have studied its function and regulation during the cellular response to DNA damage and show that this endonuclease is necessary for successful chromosome replication and cell survival in the presence of DNA lesions that interfere with replication fork progression. On the contrary, Mus81-Mms4 is not required for coping with replicative stress originated by acute treatment with hydroxyurea (HU), which causes fork stalling. Despite its requirement for dealing with DNA lesions that hinder DNA replication, Mus81-Mms4 activation is not induced by DNA damage at replication forks. Full Mus81-Mms4 activity is only acquired when cells finish S-phase and the endonuclease executes its function after the bulk of genome replication is completed. This post-replicative mode of action of Mus81-Mms4 limits its nucleolytic activity during S-phase, thus avoiding the potential cleavage of DNA substrates that could cause genomic instability during DNA replication. At the same time, it constitutes an efficient fail-safe mechanism for processing DNA intermediates that cannot be resolved by other proteins and persist after bulk DNA synthesis, which guarantees the completion of DNA repair and faithful chromosome replication when the DNA is damaged.
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spelling pubmed-37994262013-10-21 Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage Saugar, Irene Vázquez, María Victoria Gallo-Fernández, María Ortiz-Bazán, María Ángeles Segurado, Mónica Calzada, Arturo Tercero, José Antonio Nucleic Acids Res Genome Integrity, Repair and Replication The structure-specific Mus81-Eme1/Mms4 endonuclease contributes importantly to DNA repair and genome integrity maintenance. Here, using budding yeast, we have studied its function and regulation during the cellular response to DNA damage and show that this endonuclease is necessary for successful chromosome replication and cell survival in the presence of DNA lesions that interfere with replication fork progression. On the contrary, Mus81-Mms4 is not required for coping with replicative stress originated by acute treatment with hydroxyurea (HU), which causes fork stalling. Despite its requirement for dealing with DNA lesions that hinder DNA replication, Mus81-Mms4 activation is not induced by DNA damage at replication forks. Full Mus81-Mms4 activity is only acquired when cells finish S-phase and the endonuclease executes its function after the bulk of genome replication is completed. This post-replicative mode of action of Mus81-Mms4 limits its nucleolytic activity during S-phase, thus avoiding the potential cleavage of DNA substrates that could cause genomic instability during DNA replication. At the same time, it constitutes an efficient fail-safe mechanism for processing DNA intermediates that cannot be resolved by other proteins and persist after bulk DNA synthesis, which guarantees the completion of DNA repair and faithful chromosome replication when the DNA is damaged. Oxford University Press 2013-10 2013-07-30 /pmc/articles/PMC3799426/ /pubmed/23901010 http://dx.doi.org/10.1093/nar/gkt645 Text en © The Author(s) 2013. Published by Oxford University Press. http://creativecommons.org/licenses/by/3.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited.
spellingShingle Genome Integrity, Repair and Replication
Saugar, Irene
Vázquez, María Victoria
Gallo-Fernández, María
Ortiz-Bazán, María Ángeles
Segurado, Mónica
Calzada, Arturo
Tercero, José Antonio
Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage
title Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage
title_full Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage
title_fullStr Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage
title_full_unstemmed Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage
title_short Temporal regulation of the Mus81-Mms4 endonuclease ensures cell survival under conditions of DNA damage
title_sort temporal regulation of the mus81-mms4 endonuclease ensures cell survival under conditions of dna damage
topic Genome Integrity, Repair and Replication
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3799426/
https://www.ncbi.nlm.nih.gov/pubmed/23901010
http://dx.doi.org/10.1093/nar/gkt645
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