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, Songyang 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 () and Jianghong Man ()
Additional contact information
Lanjuan Mi: National Center of Biomedical Analysis
Yan Cai: National Center of Biomedical Analysis
Ji Qi: Beijing Fengtai Hospital
Lishu Chen: National Center of Biomedical Analysis
Yuanyuan Li: National Center of Biomedical Analysis
Songyang Zhang: National Center of Biomedical Analysis
Haowen Ran: National Center of Biomedical Analysis
Qinghui Qi: National Center of Biomedical Analysis
Cheng Zhang: National Center of Biomedical Analysis
Huiran Wu: National Center of Biomedical Analysis
Shuailiang Cao: National Center of Biomedical Analysis
Haohao Huang: National Center of Biomedical Analysis
Dake Xiao: National Center of Biomedical Analysis
Xinzheng Wang: National Center of Biomedical Analysis
Bohan Li: Beijing Fengtai Hospital
Jiong Xie: Beijing Fengtai Hospital
Fangye Li: First Medical Center of PLA General Hospital
Qiuying Han: National Center of Biomedical Analysis
Qiulian Wu: University of Pittsburgh Medical Center Hillman Cancer Center
Tao Li: National Center of Biomedical Analysis
Ailing Li: National Center of Biomedical Analysis
Jeremy N. Rich: University of Pittsburgh Medical Center Hillman Cancer Center
Tao Zhou: National Center of Biomedical Analysis
Jianghong Man: National Center of Biomedical Analysis

Nature Communications, 2025, vol. 16, issue 1, 1-19

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-60228-z

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