Li Xiaoqing, Gao Dexuan, Shen Fei, Chen Hengrui, Zhang Zhuqiang, He Chao, Gao Aidi, Lang Yue, Zhu Xiaozhong, Zhou Jundong, Shang Zeng-Fu, Ding Wei-Qun, Zhu Ji
Suzhou Cancer Center Core Laboratory, Nanjing Medical University Affiliated Suzhou Hospital, Suzhou, Jiangsu, China.
Department of Urology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China.
Cell Death Discov. 2023 Aug 9;9(1):291. doi: 10.1038/s41420-023-01541-8.
Radiotherapy resistance is an important and urgent challenge in the clinical management of esophageal squamous carcinoma (ESCC). However, the factors mediating the ESCC resistance to radiotherapy and its underlying molecular mechanisms are not fully clarified. Our previous studies have demonstrated the critical role of DNA polymerase iota (POLI) in ESCC development and progression, here, we aimed to investigate the involvement of POLI in ESCC radiotherapy resistance and elucidate the underlying molecular mechanism. We found that highly expressed POLI was correlated with shorter overall survival of ESCC patients received radiotherapy. Down-regulation of POLI sensitized ESCC to IR, prolonged γH2AX foci in nuclei and comet tails after IR. HR but not NHEJ repair is inhibited in POLI-deficient ESCC cells. POLI stabilizes RAD51 protein via competitively binding with and blocking the interaction between RAD51 and E3 ligase XIAP and XIAP-mediated ubiquitination. Furthermore, loss of POLI leads to the activation of GAS signaling. Our findings provide novel insight into the role of POLI in the development of radioresistance mediated by stabilizing RAD51 protein in ESCC.
放疗抵抗是食管鳞状细胞癌（ESCC）临床治疗中一项重要且紧迫的挑战。然而，介导ESCC放疗抵抗的因素及其潜在分子机制尚未完全阐明。我们之前的研究已经证明了DNA聚合酶ι（POLI）在ESCC发生发展中的关键作用，在此，我们旨在研究POLI在ESCC放疗抵抗中的作用，并阐明其潜在分子机制。我们发现，高表达的POLI与接受放疗的ESCC患者较短的总生存期相关。POLI的下调使ESCC对电离辐射（IR）敏感，延长了IR后细胞核中γH2AX焦点和彗星尾。在POLI缺陷的ESCC细胞中，同源重组（HR）而非非同源末端连接（NHEJ）修复受到抑制。POLI通过与RAD51和E3连接酶XIAP竞争性结合并阻断它们之间的相互作用以及XIAP介导的泛素化来稳定RAD51蛋白。此外，POLI的缺失导致γ干扰素激活位点（GAS）信号的激活。我们的研究结果为POLI在ESCC中通过稳定RAD51蛋白介导放疗抵抗发展中的作用提供了新的见解。
