Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain.
Cancer Research Program, Institut Mar d'Investigacions Mèdiques, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain; DSB Repair Metabolism Laboratory, The Francis Crick Institute, London NW1 1AT, UK.
Mol Cell. 2019 Aug 22;75(4):669-682.e5. doi: 10.1016/j.molcel.2019.05.036. Epub 2019 Jul 10.
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.
磷酸化 IKKα(p45) 是 IKKα 激酶的核活性形式，由 MAP 激酶 BRAF 和 TAK1 诱导，可促进肿瘤生长，而不依赖于经典的 NF-κB 信号通路。目前仍需明确 IKKα(p45) 在核内的激活来源及其下游底物。在这里，我们发现 IKKα(p45)可被 DNA 损伤快速激活，这种激活不依赖于 ATM-ATR，但依赖于 BRAF-TAK1-p38-MAPK，并且对于 ATM 的有效激活和高效 DNA 修复是必需的。消除 BRAF 或 IKKα 的活性会减弱 ATM、Chk1、MDC1、Kap1 和 53BP1 的磷酸化，损害 53BP1 和 RIF1 对 DNA 损伤部位的共募集，并抑制 53BP1 依赖性功能失调端粒的融合。此外，IKKα 或 BRAF 的抑制协同增强了 5-FU 和伊立替康消除体内化疗耐药转移性人类肿瘤的治疗潜力。我们的研究结果表明 BRAF 和 IKKα 激酶参与了 DDR，并揭示了一种用于癌症治疗的联合策略。
