Phosphorylated IKKa(p45) is a nuclear active form of the IKKa kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-¿B signaling. Insights into the sources of IKKa(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKKa(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 IKKa 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, IKKa 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 IKKa kinases in the DDR and reveal a combination strategy for cancer treatment.

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