Colomer, Carlota Margalef, Pol Villanueva, Alberto Vert, Anna Pecharroman, Irene Solé, Laura González-Farré, Mónica Alonso, Josune Montagut, Clara Martinez-Iniesta, Maria Bertran, Joan Borràs, Eva Iglesias, Mar Sabidó, Eduard Bigas, Anna Boulton, Simon J Espinosa, Lluís 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 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. ATM;BRAF;DNA-damage Repair;IKK;cancer treatment;combination therapy;ortho-xenografts;patient-derived organoids;phosphorylation;therapy resistance;Boulton FC001048;06 Biological Sciences;11 Medical and Health Sciences;Developmental Biology 2020-01-09
    https://crick.figshare.com/articles/journal_contribution/IKK_kinase_regulates_the_DNA_damage_response_and_drives_chemo-resistance_in_cancer_/11559525