Mi Lanjuan, Cai Yan, Qi Ji, Chen Lishu, Li Yuanyuan, Zhang Songyang, Ran Haowen, Qi Qinghui, Zhang Cheng, Wu Huiran, Cao Shuailiang, Huang Haohao, Xiao Dake, Wang Xinzheng, Li Bohan, Xie Jiong, Li Fangye, Han Qiuying, Wu Qiulian, Li Tao, Li Ailing, Rich Jeremy N, Zhou Tao, Man Jianghong
Nanhu Laboratory, National Center of Biomedical Analysis, Beijing, China.
School of Life and Health Sciences, Huzhou College, Huzhou, China.
Nat Commun. 2025 May 28;16(1):4941. doi: 10.1038/s41467-025-60228-z.
Glioblastoma (GB) is a highly aggressive brain tumor resistant to chemoradiotherapy, largely due to glioma stem-like cells (GSCs) with robust DNA damage repair capabilities. Here we reveal that GSCs enhance their DNA repair capacity by activating non-homologous end-joining (NHEJ) through upregulation of the apoptosis antagonizing transcription factor (AATF), thereby promoting therapeutic resistance in GB. AATF interacts with XRCC4, a core NHEJ subunit, preventing its degradation via ubiquitin-mediated proteasomal processes. Upon DNA damage, AATF undergoes phosphorylation at Ser189 by ATM, leading to its dissociation from XRCC4 and rapid recruitment of XRCC4 to DNA break sites for efficient NHEJ repair. Moreover, AATF depletion or deficient AATF phosphorylation impedes NHEJ in GSCs, sensitizing GB xenografts to chemoradiotherapy. Additionally, elevated levels of AATF inform poor prognosis in GB patients. Collectively, our findings unveil a crucial role of AATF in XRCC4-mediated NHEJ repair, and underscore targeting AATF as a potential strategy to overcome GB resistance to chemoradiotherapy.
胶质母细胞瘤（GB）是一种对放化疗具有高度抗性的侵袭性脑肿瘤，这主要归因于具有强大DNA损伤修复能力的胶质瘤干细胞（GSCs）。在此，我们发现GSCs通过上调凋亡拮抗转录因子（AATF）激活非同源末端连接（NHEJ）来增强其DNA修复能力，从而促进GB的治疗抗性。AATF与NHEJ核心亚基XRCC4相互作用，通过泛素介导的蛋白酶体过程防止其降解。DNA损伤时，AATF在Ser189位点被ATM磷酸化，导致其与XRCC4解离，并使XRCC4迅速募集到DNA断裂位点以进行高效的NHEJ修复。此外，AATF缺失或AATF磷酸化缺陷会阻碍GSCs中的NHEJ，使GB异种移植对放化疗敏感。此外，GB患者中AATF水平升高提示预后不良。总之，我们的研究结果揭示了AATF在XRCC4介导的NHEJ修复中的关键作用，并强调将AATF作为克服GB对放化疗抗性的潜在策略。
