IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer

Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be define...

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Autores: Colomer, Carlota, Margalef, Pol, Villanueva Garatachea, Alberto, Vert, Anna, Pecharroman, Irene, Sole, Laura, González Farré, Mónica, Alonso, Josune, Montagut Viladot, Clara, Martínez Iniesta, María, Bertran, Joan, Borràs, Eva, Iglesias, Mar, Sabidó Aguadé, Eduard, Bigas Salvans, Anna, Boulton, Simon J., Espinosa, Lluís
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2019
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:2445/171364
Acceso en línea:https://hdl.handle.net/2445/171364
Access Level:acceso abierto
Palabra clave:Càncer
Reparació de l'ADN
Cancer
DNA repair
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spelling IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in CancerColomer, CarlotaMargalef, PolVillanueva Garatachea, AlbertoVert, AnnaPecharroman, IreneSole, LauraGonzález Farré, MónicaAlonso, JosuneMontagut Viladot, ClaraMartínez Iniesta, MaríaBertran, JoanBorràs, EvaIglesias, MarSabidó Aguadé, EduardBigas Salvans, AnnaBoulton, Simon J.Espinosa, LluísCàncerReparació de l'ADNCancerDNA repairPhosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKα activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKα or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKα kinases in the DDR and reveal a combination strategy for cancer treatment.Cell Press2020202020192020info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion20 p.application/pdfapplication/pdfhttps://hdl.handle.net/2445/171364Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: https://doi.org/10.1016/j.molcel.2019.05.036Molecular Cell, 2019, vol. 75, num. 4, p. 669-682https://doi.org/10.1016/j.molcel.2019.05.036info:eu-repo/grantAgreement/EC/H2020/702430info:eu-repo/grantAgreement/EC/H2020/742437cc by-nc-nd (c) Colomer et al., 2019http://creativecommons.org/licenses/by-nc-nd/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1713642026-05-29T05:05:01Z
dc.title.none.fl_str_mv IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
title IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
spellingShingle IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
Colomer, Carlota
Càncer
Reparació de l'ADN
Cancer
DNA repair
title_short IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
title_full IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
title_fullStr IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
title_full_unstemmed IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
title_sort IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
dc.creator.none.fl_str_mv Colomer, Carlota
Margalef, Pol
Villanueva Garatachea, Alberto
Vert, Anna
Pecharroman, Irene
Sole, Laura
González Farré, Mónica
Alonso, Josune
Montagut Viladot, Clara
Martínez Iniesta, María
Bertran, Joan
Borràs, Eva
Iglesias, Mar
Sabidó Aguadé, Eduard
Bigas Salvans, Anna
Boulton, Simon J.
Espinosa, Lluís
author Colomer, Carlota
author_facet Colomer, Carlota
Margalef, Pol
Villanueva Garatachea, Alberto
Vert, Anna
Pecharroman, Irene
Sole, Laura
González Farré, Mónica
Alonso, Josune
Montagut Viladot, Clara
Martínez Iniesta, María
Bertran, Joan
Borràs, Eva
Iglesias, Mar
Sabidó Aguadé, Eduard
Bigas Salvans, Anna
Boulton, Simon J.
Espinosa, Lluís
author_role author
author2 Margalef, Pol
Villanueva Garatachea, Alberto
Vert, Anna
Pecharroman, Irene
Sole, Laura
González Farré, Mónica
Alonso, Josune
Montagut Viladot, Clara
Martínez Iniesta, María
Bertran, Joan
Borràs, Eva
Iglesias, Mar
Sabidó Aguadé, Eduard
Bigas Salvans, Anna
Boulton, Simon J.
Espinosa, Lluís
author2_role author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Càncer
Reparació de l'ADN
Cancer
DNA repair
topic Càncer
Reparació de l'ADN
Cancer
DNA repair
description Phosphorylated IKKα(p45) is a nuclear active form of the IKKα kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-κB signaling. Insights into the sources of IKKα(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKα(p45) is rapidly activated by DNA damage independent of ATM-ATR, but dependent on BRAF-TAK1-p38-MAPK, and is required for robust ATM activation and efficient DNA repair. Abolishing BRAF or IKKα activity attenuates ATM, Chk1, MDC1, Kap1, and 53BP1 phosphorylation, compromises 53BP1 and RIF1 co-recruitment to sites of DNA lesions, and inhibits 53BP1-dependent fusion of dysfunctional telomeres. Furthermore, IKKα or BRAF inhibition synergistically enhances the therapeutic potential of 5-FU and irinotecan to eradicate chemotherapy-resistant metastatic human tumors in vivo. Our results implicate BRAF and IKKα kinases in the DDR and reveal a combination strategy for cancer treatment.
publishDate 2019
dc.date.none.fl_str_mv 2019
2020
2020
2020
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/2445/171364
url https://hdl.handle.net/2445/171364
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: https://doi.org/10.1016/j.molcel.2019.05.036
Molecular Cell, 2019, vol. 75, num. 4, p. 669-682
https://doi.org/10.1016/j.molcel.2019.05.036
info:eu-repo/grantAgreement/EC/H2020/702430
info:eu-repo/grantAgreement/EC/H2020/742437
dc.rights.none.fl_str_mv cc by-nc-nd (c) Colomer et al., 2019
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by-nc-nd (c) Colomer et al., 2019
http://creativecommons.org/licenses/by-nc-nd/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 20 p.
application/pdf
application/pdf
dc.publisher.none.fl_str_mv Cell Press
publisher.none.fl_str_mv Cell Press
dc.source.none.fl_str_mv Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))
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
_version_ 1869425077507850240
score 15,811543

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