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Title: IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
Author: Colomer, Carlota
Margalef, Pol
Villanueva Garatachea, Alberto
Vert, Anna
Pecharroman, Irene
Sole, Laura
González Farré, Mónica
Alonso, Josune
Montagut, Clara
Martínez Iniesta, María
Bertran, Joan
Borràs, Eva
Iglesias, Mar
Sabidó, Eduard
Bigas Salvans, Anna
Boulton, Simon J.
Espinosa, Lluís
Keywords: Càncer
Reparació de l'ADN
DNA repair
Issue Date: 22-Aug-2019
Publisher: Cell Press
Abstract: 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.
Note: Reproducció del document publicat a:
It is part of: Molecular Cell, 2019, vol. 75, num. 4, p. 669-682
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Appears in Collections:Articles publicats en revistes (Institut d'lnvestigació Biomèdica de Bellvitge (IDIBELL))

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