S-phase checkpoint protects from aberrant replication fork processing and degradation

Replication stress, a hallmark of cancer cells, is detected by checkpoint mechanisms that trigger a range of cellular responses. Among these, the preservation of replication fork integrity is crucial for ensuring survival in the presence of DNA damage. In budding yeast checkpoint mutants, DNA damage...

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Autores: Núñez-Martín, Iván, Drury, Lucy S., Martinez-Jiménez, María, Blanco, Luis, Diffley, John F. X., Aguilera López, Andrés, Gómez González, Belén
Tipo de documento: artigo
Estado:Versão publicada
Data de publicação:2025
País:España
Recursos:Universidad de Sevilla (US)
Repositório:idUS. Depósito de Investigación de la Universidad de Sevilla
OAI Identifier:oai:idus.us.es:11441/177442
Acesso em linha:https://hdl.handle.net/11441/177442
https://doi.org/10.1093/nar/gkaf707
Access Level:Acceso aberto
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spelling S-phase checkpoint protects from aberrant replication fork processing and degradationNúñez-Martín, IvánDrury, Lucy S.Martinez-Jiménez, MaríaBlanco, LuisDiffley, John F. X.Aguilera López, AndrésGómez González, BelénReplication stress, a hallmark of cancer cells, is detected by checkpoint mechanisms that trigger a range of cellular responses. Among these, the preservation of replication fork integrity is crucial for ensuring survival in the presence of DNA damage. In budding yeast checkpoint mutants, DNA damage leads to irreversible replication fork arrest and subsequent cell death, though the underlying mechanism remains unclear. Our study reveals that several DNA processing factors, including Rad51, the Rad5 HIRAN and helicase domains, and the catalytic activity of Mus81, contribute to this lethality. Nevertheless, their roles are masked by their essential functions in cell survival after damage removal. Additionally, we show that these factors, along with Exo1, drive the gradual degradation of nascent DNA at replication forks upon DNA damage. Notably, this degradation can be mitigated by expression of human PrimPol, which is absent in yeast. These findings suggest that the essential role of S-phase checkpoints upon DNA damage is to safeguard stalled replication forks from aberrant processing, thereby preserving nascent DNA integrity.Oxford University PressGenéticaJunta de AndalucíaAgencia Estatal de Investigación. EspañaFundación de Investigación Universidad de SevillaMinisterio de Ciencia, Innovación y Universidades (MICIU). España2025info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersionapplication/pdfapplication/pdfhttps://hdl.handle.net/11441/177442https://doi.org/10.1093/nar/gkaf707reponame:idUS. Depósito de Investigación de la Universidad de Sevillainstname:Universidad de Sevilla (US)InglésNucleic Acids Research, 53 (14), gkaf707.US-1380058PID2019- 104270GB-I00/BMCFIUS22/01 788PID2021-125966OB-I00https://doi.org/10.1093/nar/gkaf707info:eu-repo/semantics/openAccessoai:idus.us.es:11441/1774422026-06-17T12:51:07Z
dc.title.none.fl_str_mv S-phase checkpoint protects from aberrant replication fork processing and degradation
title S-phase checkpoint protects from aberrant replication fork processing and degradation
spellingShingle S-phase checkpoint protects from aberrant replication fork processing and degradation
Núñez-Martín, Iván
title_short S-phase checkpoint protects from aberrant replication fork processing and degradation
title_full S-phase checkpoint protects from aberrant replication fork processing and degradation
title_fullStr S-phase checkpoint protects from aberrant replication fork processing and degradation
title_full_unstemmed S-phase checkpoint protects from aberrant replication fork processing and degradation
title_sort S-phase checkpoint protects from aberrant replication fork processing and degradation
dc.creator.none.fl_str_mv Núñez-Martín, Iván
Drury, Lucy S.
Martinez-Jiménez, María
Blanco, Luis
Diffley, John F. X.
Aguilera López, Andrés
Gómez González, Belén
author Núñez-Martín, Iván
author_facet Núñez-Martín, Iván
Drury, Lucy S.
Martinez-Jiménez, María
Blanco, Luis
Diffley, John F. X.
Aguilera López, Andrés
Gómez González, Belén
author_role author
author2 Drury, Lucy S.
Martinez-Jiménez, María
Blanco, Luis
Diffley, John F. X.
Aguilera López, Andrés
Gómez González, Belén
author2_role author
author
author
author
author
author
dc.contributor.none.fl_str_mv Genética
Junta de Andalucía
Agencia Estatal de Investigación. España
Fundación de Investigación Universidad de Sevilla
Ministerio de Ciencia, Innovación y Universidades (MICIU). España
description Replication stress, a hallmark of cancer cells, is detected by checkpoint mechanisms that trigger a range of cellular responses. Among these, the preservation of replication fork integrity is crucial for ensuring survival in the presence of DNA damage. In budding yeast checkpoint mutants, DNA damage leads to irreversible replication fork arrest and subsequent cell death, though the underlying mechanism remains unclear. Our study reveals that several DNA processing factors, including Rad51, the Rad5 HIRAN and helicase domains, and the catalytic activity of Mus81, contribute to this lethality. Nevertheless, their roles are masked by their essential functions in cell survival after damage removal. Additionally, we show that these factors, along with Exo1, drive the gradual degradation of nascent DNA at replication forks upon DNA damage. Notably, this degradation can be mitigated by expression of human PrimPol, which is absent in yeast. These findings suggest that the essential role of S-phase checkpoints upon DNA damage is to safeguard stalled replication forks from aberrant processing, thereby preserving nascent DNA integrity.
publishDate 2025
dc.date.none.fl_str_mv 2025
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/11441/177442
https://doi.org/10.1093/nar/gkaf707
url https://hdl.handle.net/11441/177442
https://doi.org/10.1093/nar/gkaf707
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Nucleic Acids Research, 53 (14), gkaf707.
US-1380058
PID2019- 104270GB-I00/BMC
FIUS22/01 788
PID2021-125966OB-I00
https://doi.org/10.1093/nar/gkaf707
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
application/pdf
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:idUS. Depósito de Investigación de la Universidad de Sevilla
instname:Universidad de Sevilla (US)
instname_str Universidad de Sevilla (US)
reponame_str idUS. Depósito de Investigación de la Universidad de Sevilla
collection idUS. Depósito de Investigación de la Universidad de Sevilla
repository.name.fl_str_mv
repository.mail.fl_str_mv
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