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RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress

Solving the problems that replication forks encounter when synthesizing DNA is essential to prevent genomic instability. Besides their role in DNA repair in the G2 phase, several homologous recombination proteins, specifically RAD51, have prominent roles in the S phase. Using different cellular mode...

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Autores principales: Feu, Sonia, Unzueta, Fernando, Ercilla, Amaia, Pérez-Venteo, Alejandro, Jaumot, Montserrat, Agell, Neus
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377619/
https://www.ncbi.nlm.nih.gov/pubmed/35969531
http://dx.doi.org/10.1371/journal.pone.0266645
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author Feu, Sonia
Unzueta, Fernando
Ercilla, Amaia
Pérez-Venteo, Alejandro
Jaumot, Montserrat
Agell, Neus
author_facet Feu, Sonia
Unzueta, Fernando
Ercilla, Amaia
Pérez-Venteo, Alejandro
Jaumot, Montserrat
Agell, Neus
author_sort Feu, Sonia
collection PubMed
description Solving the problems that replication forks encounter when synthesizing DNA is essential to prevent genomic instability. Besides their role in DNA repair in the G2 phase, several homologous recombination proteins, specifically RAD51, have prominent roles in the S phase. Using different cellular models, RAD51 has been shown not only to be present at ongoing and arrested replication forks but also to be involved in nascent DNA protection and replication fork restart. Through pharmacological inhibition, here we study the specific role of RAD51 in the S phase. RAD51 inhibition in non-transformed cell lines did not have a significant effect on replication fork progression under non-perturbed conditions, but when the same cells were subjected to replication stress, RAD51 became necessary to maintain replication fork progression. Notably, the inhibition or depletion of RAD51 did not compromise fork integrity when subjected to hydroxyurea treatment. RAD51 inhibition also did not decrease the ability to restart, but rather compromised fork progression during reinitiation. In agreement with the presence of basal replication stress in human colorectal cancer cells, RAD51 inhibition reduced replication fork speed in these cells and increased γH2Ax foci under control conditions. These alterations could have resulted from the reduced association of DNA polymerase α to chromatin, as observed when inhibiting RAD51. It may be possible to exploit the differential dependence of non-transformed cells versus colorectal cancer cells on RAD51 activity under basal conditions to design new therapies that specifically target cancer cells.
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spelling pubmed-93776192022-08-16 RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress Feu, Sonia Unzueta, Fernando Ercilla, Amaia Pérez-Venteo, Alejandro Jaumot, Montserrat Agell, Neus PLoS One Research Article Solving the problems that replication forks encounter when synthesizing DNA is essential to prevent genomic instability. Besides their role in DNA repair in the G2 phase, several homologous recombination proteins, specifically RAD51, have prominent roles in the S phase. Using different cellular models, RAD51 has been shown not only to be present at ongoing and arrested replication forks but also to be involved in nascent DNA protection and replication fork restart. Through pharmacological inhibition, here we study the specific role of RAD51 in the S phase. RAD51 inhibition in non-transformed cell lines did not have a significant effect on replication fork progression under non-perturbed conditions, but when the same cells were subjected to replication stress, RAD51 became necessary to maintain replication fork progression. Notably, the inhibition or depletion of RAD51 did not compromise fork integrity when subjected to hydroxyurea treatment. RAD51 inhibition also did not decrease the ability to restart, but rather compromised fork progression during reinitiation. In agreement with the presence of basal replication stress in human colorectal cancer cells, RAD51 inhibition reduced replication fork speed in these cells and increased γH2Ax foci under control conditions. These alterations could have resulted from the reduced association of DNA polymerase α to chromatin, as observed when inhibiting RAD51. It may be possible to exploit the differential dependence of non-transformed cells versus colorectal cancer cells on RAD51 activity under basal conditions to design new therapies that specifically target cancer cells. Public Library of Science 2022-08-15 /pmc/articles/PMC9377619/ /pubmed/35969531 http://dx.doi.org/10.1371/journal.pone.0266645 Text en © 2022 Feu et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Feu, Sonia
Unzueta, Fernando
Ercilla, Amaia
Pérez-Venteo, Alejandro
Jaumot, Montserrat
Agell, Neus
RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress
title RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress
title_full RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress
title_fullStr RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress
title_full_unstemmed RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress
title_short RAD51 is a druggable target that sustains replication fork progression upon DNA replication stress
title_sort rad51 is a druggable target that sustains replication fork progression upon dna replication stress
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9377619/
https://www.ncbi.nlm.nih.gov/pubmed/35969531
http://dx.doi.org/10.1371/journal.pone.0266645
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