Elevated nonhomologous end-joining by AATF enables efficient DNA damage repair and therapeutic resistance in glioblastoma
Lanjuan Mi, Yan Cai, Ji Qi, Lishu Chen, Yuanyuan Li, Song‐Yang Zhang, Haowen Ran, Qinghui Qi, Cheng Zhang, Huiran Wu, Shuailiang Cao, Haohao Huang, Dake Xiao, Xinzheng Wang, Bohan Li, Jiong Xie, Fangye Li, Qiuying Han, Qiulian Wu, Tao Li, Ailing Li, Jeremy N. Rich, Tao Zhou, Jianghong Man
Abstract
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. Glioma stem-like cells (GSCs) contribute to therapeutic resistance via enhanced capability of DNA damage repair. Here the authors identify that the upregulated transcription factor AATF in GSCs modulates the stability and release of XRCC4 protein to promote DNA repair and resistance to radiotherapy.