IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
IKKα Kinase Regulates the DNA Damage Response and Drives Chemo-resistance in Cancer
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DOI：
10.1016/j.molcel.2019.05.036
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发表时间：
2019-08-22
期刊：
影响因子：
16
通讯作者：
Espinosa, Lluis
中科院分区：
文献类型：
--
作者：
Colomer, Carlota;Margalef, Pol;Espinosa, Lluis
磷酸化IKK α（p45）是IKK α激酶的一种核活性形式，由MAP激酶BRAF和TAK 1诱导，促进肿瘤生长，不依赖于典型的NF-κ B信号传导。对IKK α（p45）激活的来源及其在细胞核中的下游底物的了解仍有待确定。在这里，我们发现IKK α（p45）被DNA损伤快速激活，不依赖于ATM-ATR，但依赖于BRAF-TAK 1-p38-MAPK，并且是稳定的ATM激活和有效的DNA修复所必需的。消除BRAF或IKK α活性会减弱ATM、Chk 1、MDC 1、Kap 1和53 BP 1的磷酸化，损害53 BP 1和RIF 1共同募集到DNA损伤位点，并抑制53 BP 1依赖性功能失调的端粒融合。此外，IKK α或BRAF抑制可协同增强5-FU和伊立替康在体内根除化疗耐药转移性人类肿瘤的治疗潜力。我们的研究结果暗示了DDR中的BRAF和IKK α激酶，并揭示了癌症治疗的联合策略。
Phosphorylated IKK alpha(p45) is a nuclear active form of the IKK alpha kinase that is induced by the MAP kinases BRAF and TAK1 and promotes tumor growth independent of canonical NF-kappa B signaling. Insights into the sources of IKK alpha(p45) activation and its downstream substrates in the nucleus remain to be defined. Here, we discover that IKK alpha(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 IKK alpha 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, IKK alpha 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 IKK alpha kinases in the DDR and reveal a combination strategy for cancer treatment.