The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest

Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication chec...

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Detalles Bibliográficos
Autores: Llopis, Alba, Salvador, Noelia, Ercilla Eguiarte, Amaia, Guaita-Esteruelas, Sandra, Barco Barrantes, Ivan del, Gupta, Jalaj, Gaestel, Matthias, Davis, Roger J., Nebreda, Àngel R., Agell i Jané, Neus
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2012
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/34095
Acceso en línea:https://hdl.handle.net/2445/34095
Access Level:acceso abierto
Palabra clave:Proteïnes quinases
ADN
Mitosi
Protein kinases
DNA
Mitosis
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spelling The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrestLlopis, AlbaSalvador, NoeliaErcilla Eguiarte, AmaiaGuaita-Esteruelas, SandraBarco Barrantes, Ivan delGupta, JalajGaestel, MatthiasDavis, Roger J.Nebreda, Àngel R.Agell i Jané, NeusProteïnes quinasesADNMitosiProtein kinasesDNAMitosisAccurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G₂/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38α and p38β isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, there by preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA.Landes Bioscience2013201320122013info:eu-repo/semantics/articleinfo:eu-repo/semantics/acceptedVersion41 p.application/pdfhttps://hdl.handle.net/2445/34095Articles publicats en revistes (Biomedicina)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésVersió postprint del document publicat a: http://dx.doi.org/10.4161/cc.21917Cell Cycle, 2012, vol. 11, num. 19, p. 3627-3637http://dx.doi.org/10.4161/cc.21917(c) Landes Bioscience , 2012info:eu-repo/semantics/openAccessoai:recercat.cat:2445/340952026-05-29T05:05:01Z
dc.title.none.fl_str_mv The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
title The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
spellingShingle The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
Llopis, Alba
Proteïnes quinases
ADN
Mitosi
Protein kinases
DNA
Mitosis
title_short The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
title_full The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
title_fullStr The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
title_full_unstemmed The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
title_sort The stress-activated protein kinases p38α/β and JNK1/2 cooperate with Chk1 to inhibit mitotic entry upon DNA replication arrest
dc.creator.none.fl_str_mv Llopis, Alba
Salvador, Noelia
Ercilla Eguiarte, Amaia
Guaita-Esteruelas, Sandra
Barco Barrantes, Ivan del
Gupta, Jalaj
Gaestel, Matthias
Davis, Roger J.
Nebreda, Àngel R.
Agell i Jané, Neus
author Llopis, Alba
author_facet Llopis, Alba
Salvador, Noelia
Ercilla Eguiarte, Amaia
Guaita-Esteruelas, Sandra
Barco Barrantes, Ivan del
Gupta, Jalaj
Gaestel, Matthias
Davis, Roger J.
Nebreda, Àngel R.
Agell i Jané, Neus
author_role author
author2 Salvador, Noelia
Ercilla Eguiarte, Amaia
Guaita-Esteruelas, Sandra
Barco Barrantes, Ivan del
Gupta, Jalaj
Gaestel, Matthias
Davis, Roger J.
Nebreda, Àngel R.
Agell i Jané, Neus
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Proteïnes quinases
ADN
Mitosi
Protein kinases
DNA
Mitosis
topic Proteïnes quinases
ADN
Mitosi
Protein kinases
DNA
Mitosis
description Accurate DNA replication is crucial for the maintenance of genome integrity. To this aim, cells have evolved complex surveillance mechanisms to prevent mitotic entry in the presence of partially replicated DNA. ATR and Chk1 are key elements in the signal transduction pathways of DNA replication checkpoint; however, other kinases also make significant contributions. We show here that the stress kinases p38 and JNK are activated when DNA replication is blocked, and that their activity allows S/M, but not G₂/M, checkpoint maintenance when Chk1 is inhibited. Activation of both kinases by DNA replication inhibition is not mediated by the caffeine-sensitive kinases ATR or ATM. Phosphorylation of MKK3/6 and MKK4, p38 and JNK upstream kinases was also observed upon DNA replication inhibition. Using a genetic approach, we dissected the p38 pathway and showed that both p38α and p38β isoforms collaborate to inhibit mitotic entry. We further defined MKK3/6 and MK2/3 as the key upstream and downstream elements in the p38 signaling cascade after replication arrest. Accordingly, we found that the stress signaling pathways collaborate with Chk1 to keep cyclin B1/Cdk1 complexes inactive when DNA replication is inhibited, there by preventing cell cycle progression when DNA replication is stalled. Our results show a complex response to replication stress, where multiple pathways are activated and fulfill overlapping roles to prevent mitotic entry with unreplicated DNA.
publishDate 2012
dc.date.none.fl_str_mv 2012
2013
2013
2013
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/acceptedVersion
format article
status_str acceptedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/34095
url https://hdl.handle.net/2445/34095
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Versió postprint del document publicat a: http://dx.doi.org/10.4161/cc.21917
Cell Cycle, 2012, vol. 11, num. 19, p. 3627-3637
http://dx.doi.org/10.4161/cc.21917
dc.rights.none.fl_str_mv (c) Landes Bioscience , 2012
info:eu-repo/semantics/openAccess
rights_invalid_str_mv (c) Landes Bioscience , 2012
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 41 p.
application/pdf
dc.publisher.none.fl_str_mv Landes Bioscience
publisher.none.fl_str_mv Landes Bioscience
dc.source.none.fl_str_mv Articles publicats en revistes (Biomedicina)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,228081

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