Alonso-Marañón Josune, Solé Laura, Álvarez-Villanueva Daniel, Maqueda María, Lobo-Jarne Teresa, Montoto Ángela, Yélamos Jose, Borràs Eva, Uraga Leire, Hooper Christopher, Sabidó Eduard, Miyamoto Shigeki, Bigas Anna, Espinosa Lluís
Cancer Research Program, Hospital del Mar Research Institute, CIBERONC, Hospital del Mar, Doctor Aiguader 88, Barcelona 08003, Spain.
Chemoresistance and Predictive Factors Group, Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO), Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet del Llobregat, Barcelona 08908, Spain.
Sci Signal. 2025 Mar 11;18(877):eadr0128. doi: 10.1126/scisignal.adr0128.
The DNA damage repair kinase ATM is phosphorylated by the NF-κB pathway kinase IKKα, resulting in enhanced DNA damage repair through the nonhomologous end-joining pathway. Thus, inhibition of IKKα enhances the efficacy of cancer therapy based on inducing DNA damage. Here, we found a role for the IKK regulatory subunit NEMO in DNA damage repair mediated by ATM and IKKα. Exposure to damaging agents induced the interaction of NEMO with a preformed ATM-IKKα complex, which was required to target active ATM and IKKα to chromatin for efficient DNA damage repair but not for activating ATM. Recognition of damaged DNA by the IKKα-NEMO-ATM complex was facilitated by the interaction between NEMO and histones and depended on the ADP ribosylation of histones by the enzyme PARP1. NEMO-deficient cells showed increased activity of the kinase ATR, and inhibition of ATR potentiated the effect of chemotherapy in cells lacking NEMO or IKKα. Bioinformatic analysis of colorectal cancer datasets demonstrated that the expression of genes encoding IKKα, NEMO, and ATM correlated with poor patient prognosis, suggesting that the mechanism linking these three elements may be clinically relevant.
DNA损伤修复激酶ATM被核因子κB途径激酶IKKα磷酸化，从而通过非同源末端连接途径增强DNA损伤修复。因此，抑制IKKα可提高基于诱导DNA损伤的癌症治疗效果。在此，我们发现IKK调节亚基NEMO在由ATM和IKKα介导的DNA损伤修复中发挥作用。暴露于损伤剂会诱导NEMO与预先形成的ATM-IKKα复合物相互作用，这是将活性ATM和IKKα靶向染色质以进行高效DNA损伤修复所必需的，但并非激活ATM所必需。IKKα-NEMO-ATM复合物对受损DNA的识别因NEMO与组蛋白之间的相互作用而得到促进，并且依赖于酶PARP1对组蛋白的ADP核糖基化作用。NEMO缺陷细胞显示激酶ATR的活性增加，并且抑制ATR可增强化疗对缺乏NEMO或IKKα的细胞的作用。对结直肠癌数据集的生物信息学分析表明，编码IKKα、NEMO和ATM的基因表达与患者预后不良相关，这表明连接这三个元件的机制可能具有临床相关性。
