IDEAS home Printed from https://ideas.repec.org/a/nat/natcom/v16y2025i1d10.1038_s41467-025-60228-z.html
   My bibliography  Save this article

Elevated nonhomologous end-joining by AATF enables efficient DNA damage repair and therapeutic resistance in glioblastoma

Author

Listed:
  • Lanjuan Mi

    (National Center of Biomedical Analysis
    Huzhou College)

  • 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
    General Hospital of Central Theater Command of Chinese People’s Liberation Army)

  • Dake Xiao

    (National Center of Biomedical Analysis
    Capital Medical University)

  • 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
    University of Pittsburgh Medical 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
    University of Pittsburgh Medical Center)

  • Tao Zhou

    (National Center of Biomedical Analysis)

  • Jianghong Man

    (National Center of Biomedical Analysis)

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.

Suggested Citation

  • 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 & Ji, 2025. "Elevated nonhomologous end-joining by AATF enables efficient DNA damage repair and therapeutic resistance in glioblastoma," Nature Communications, Nature, vol. 16(1), pages 1-19, December.
    • Handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60228-z
    DOI: 10.1038/s41467-025-60228-z
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/s41467-025-60228-z
    File Function: Abstract
    Download Restriction: no
    File URL: https://libkey.io/10.1038/s41467-025-60228-z?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    References listed on IDEAS

    as
    1. Catherine T. Yan & Cristian Boboila & Ellen Kris Souza & Sonia Franco & Thomas R. Hickernell & Michael Murphy & Sunil Gumaste & Mark Geyer & Ali A. Zarrin & John P. Manis & Klaus Rajewsky & Frederick , 2007. "IgH class switching and translocations use a robust non-classical end-joining pathway," Nature, Nature, vol. 449(7161), pages 478-482, September.
    2. Ulf Grawunder & Matthias Wilm & Xiantuo Wu & Peter Kulesza & Thomas E. Wilson & Matthias Mann & Michael R. Lieber, 1997. "Activity of DNA ligase IV stimulated by complex formation with XRCC4 protein in mammalian cells," Nature, Nature, vol. 388(6641), pages 492-495, July.
    3. Haohao Huang & Songyang Zhang & Yuanyuan Li & Zhaodan Liu & Lanjuan Mi & Yan Cai & Xinzheng Wang & Lishu Chen & Haowen Ran & Dake Xiao & Fangye Li & Jiaqi Wu & Tingting Li & Qiuying Han & Liang Chen &, 2021. "Suppression of mitochondrial ROS by prohibitin drives glioblastoma progression and therapeutic resistance," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    4. Youn-Jung Kang & Barbara Balter & Eva Csizmadia & Brian Haas & Himanshu Sharma & Roderick Bronson & Catherine T. Yan, 2017. "Contribution of classical end-joining to PTEN inactivation in p53-mediated glioblastoma formation and drug-resistant survival," Nature Communications, Nature, vol. 8(1), pages 1-15, April.
    5. Yihan Peng & Qingchao Liao & Wei Tan & Changmin Peng & Zhaohua Hu & Yali Chen & Zhuqing Li & Jing Li & Bei Zhen & Wenge Zhu & Xiangpan Li & Yi Yao & Qibin Song & Chengsheng Liu & Xiangdong Qi & Fuchu , 2019. "The deubiquitylating enzyme USP15 regulates homologous recombination repair and cancer cell response to PARP inhibitors," Nature Communications, Nature, vol. 10(1), pages 1-15, December.
    6. Sheila K. Singh & Cynthia Hawkins & Ian D. Clarke & Jeremy A. Squire & Jane Bayani & Takuichiro Hide & R. Mark Henkelman & Michael D. Cusimano & Peter B. Dirks, 2004. "Identification of human brain tumour initiating cells," Nature, Nature, vol. 432(7015), pages 396-401, November.
    7. Weixing Zhao & Justin B. Steinfeld & Fengshan Liang & Xiaoyong Chen & David G. Maranon & Chu Jian Ma & Youngho Kwon & Timsi Rao & Weibin Wang & Chen Sheng & Xuemei Song & Yanhong Deng & Judit Jimenez-, 2017. "BRCA1–BARD1 promotes RAD51-mediated homologous DNA pairing," Nature, Nature, vol. 550(7676), pages 360-365, October.
    8. Shideng Bao & Qiulian Wu & Roger E. McLendon & Yueling Hao & Qing Shi & Anita B. Hjelmeland & Mark W. Dewhirst & Darell D. Bigner & Jeremy N. Rich, 2006. "Glioma stem cells promote radioresistance by preferential activation of the DNA damage response," Nature, Nature, vol. 444(7120), pages 756-760, December.
    Full references (including those not matched with items on IDEAS)

    Most related items

    These are the items that most often cite the same works as this one and are cited by the same works as this one.
    1. Paweł Wańkowicz & Przemysław Nowacki & Bogusław Machaliński & Dorota Rogińska, 2019. "Biomarkers of Cancer Stem Cells in Glioblastoma Multiforme and Histological Picture of Cancer," Biomedical Journal of Scientific & Technical Research, Biomedical Research Network+, LLC, vol. 23(3), pages 17365-17368, December.
    2. Min Kyung Lee & Nasim Azizgolshani & Joshua A. Shapiro & Lananh N. Nguyen & Fred W. Kolling & George J. Zanazzi & Hildreth Robert Frost & Brock C. Christensen, 2024. "Identifying tumor type and cell type-specific gene expression alterations in pediatric central nervous system tumors," Nature Communications, Nature, vol. 15(1), pages 1-14, December.
    3. Jun Liu & Xiaoying Wang & Ann T. Chen & Xingchun Gao & Benjamin T. Himes & Hongyi Zhang & Zeming Chen & Jianhui Wang & Wendy C. Sheu & Gang Deng & Yang Xiao & Pan Zou & Shenqi Zhang & Fuyao Liu & Yong, 2022. "ZNF117 regulates glioblastoma stem cell differentiation towards oligodendroglial lineage," Nature Communications, Nature, vol. 13(1), pages 1-10, December.
    4. Michelle M. Kameda-Smith & Helen Zhu & En-Ching Luo & Yujin Suk & Agata Xella & Brian Yee & Chirayu Chokshi & Sansi Xing & Frederick Tan & Raymond G. Fox & Ashley A. Adile & David Bakhshinyan & Kevin , 2022. "Characterization of an RNA binding protein interactome reveals a context-specific post-transcriptional landscape of MYC-amplified medulloblastoma," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    5. Weiwei Lin & Rui Niu & Seong-Min Park & Yan Zou & Sung Soo Kim & Xue Xia & Songge Xing & Qingshan Yang & Xinhong Sun & Zheng Yuan & Shuchang Zhou & Dongya Zhang & Hyung Joon Kwon & Saewhan Park & Chan, 2023. "IGFBP5 is an ROR1 ligand promoting glioblastoma invasion via ROR1/HER2-CREB signaling axis," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    6. Faye M. Walker & Lays Martin Sobral & Etienne Danis & Bridget Sanford & Sahiti Donthula & Ilango Balakrishnan & Dong Wang & Angela Pierce & Sana D. Karam & Soudabeh Kargar & Natalie J. Serkova & Nicho, 2024. "Rapid P-TEFb-dependent transcriptional reorganization underpins the glioma adaptive response to radiotherapy," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    7. Tatenda Mahlokozera & Bhuvic Patel & Hao Chen & Patrick Desouza & Xuan Qu & Diane D. Mao & Daniel Hafez & Wei Yang & Rukayat Taiwo & Mounica Paturu & Afshin Salehi & Amit D. Gujar & Gavin P. Dunn & Ni, 2021. "Competitive binding of E3 ligases TRIM26 and WWP2 controls SOX2 in glioblastoma," Nature Communications, Nature, vol. 12(1), pages 1-16, December.
    8. Zita Gál & Stavroula Boukoura & Kezia Catharina Oxe & Sara Badawi & Blanca Nieto & Lea Milling Korsholm & Sille Blangstrup Geisler & Ekaterina Dulina & Anna Vestergaard Rasmussen & Christina Dahl & We, 2024. "Hyper-recombination in ribosomal DNA is driven by long-range resection-independent RAD51 accumulation," Nature Communications, Nature, vol. 15(1), pages 1-16, December.
    9. Yuxin Huang & Wenjing Li & Tzeh Foo & Jae-Hoon Ji & Bo Wu & Nozomi Tomimatsu & Qingming Fang & Boya Gao & Melissa Long & Jingfei Xu & Rouf Maqbool & Bipasha Mukherjee & Tengyang Ni & Salvador Alejo & , 2024. "DSS1 restrains BRCA2’s engagement with dsDNA for homologous recombination, replication fork protection, and R-loop homeostasis," Nature Communications, Nature, vol. 15(1), pages 1-17, December.
    10. Sebastien Martinez & Shifei Wu & Michael Geuenich & Ahmad Malik & Ramona Weber & Tristan Woo & Amy Zhang & Gun Ho Jang & Dzana Dervovic & Khalid N. Al-Zahrani & Ricky Tsai & Nassima Fodil & Philippe G, 2024. "In vivo CRISPR screens reveal SCAF1 and USP15 as drivers of pancreatic cancer," Nature Communications, Nature, vol. 15(1), pages 1-15, December.
    11. Ravinder K. Bahia & Xiaoguang Hao & Rozina Hassam & Orsolya Cseh & Danielle A. Bozek & H. Artee Luchman & Samuel Weiss, 2023. "Epigenetic and molecular coordination between HDAC2 and SMAD3-SKI regulates essential brain tumour stem cell characteristics," Nature Communications, Nature, vol. 14(1), pages 1-20, December.
    12. George E. Ronson & Katarzyna Starowicz & Elizabeth J. Anthony & Ann Liza Piberger & Lucy C. Clarke & Alexander J. Garvin & Andrew D. Beggs & Celina M. Whalley & Matthew J. Edmonds & James F. J. Beesle, 2023. "Mechanisms of synthetic lethality between BRCA1/2 and 53BP1 deficiencies and DNA polymerase theta targeting," Nature Communications, Nature, vol. 14(1), pages 1-16, December.
    13. Scisung Chung & Mi-Sun Kang & Dauren S. Alimbetov & Gil-Im Mun & Na-Oh Yunn & Yunjin Kim & Byung-Gyu Kim & Minwoo Wie & Eun A. Lee & Jae Sun Ra & Jung-Min Oh & Donghyun Lee & Keondo Lee & Jihan Kim & , 2022. "Regulation of BRCA1 stability through the tandem UBX domains of isoleucyl-tRNA synthetase 1," Nature Communications, Nature, vol. 13(1), pages 1-14, December.
    14. Bianca L. Myers & Kathryn J. Brayer & Luis E. Paez-Beltran & Estrella Villicana & Matthew S. Keith & Hideaki Suzuki & Jessie Newville & Rebekka H. Anderson & Yunee Lo & Conner M. Mertz & Rahul K. Koll, 2024. "Transcription factors ASCL1 and OLIG2 drive glioblastoma initiation and co-regulate tumor cell types and migration," Nature Communications, Nature, vol. 15(1), pages 1-21, December.
    15. F. Nadalin & M. J. Marzi & M. Pirra Piscazzi & P. Fuentes-Bravo & S. Procaccia & M. Climent & P. Bonetti & C. Rubolino & B. Giuliani & I. Papatheodorou & J. C. Marioni & F. Nicassio, 2024. "Multi-omic lineage tracing predicts the transcriptional, epigenetic and genetic determinants of cancer evolution," Nature Communications, Nature, vol. 15(1), pages 1-23, December.
    16. Shicai Chen & Xinming Song & Zhihui Chen & Xinxin Li & Mingzhe Li & Haiying Liu & Jianchang Li, 2013. "CD133 Expression and the Prognosis of Colorectal Cancer: A Systematic Review and Meta-Analysis," PLOS ONE, Public Library of Science, vol. 8(2), pages 1-9, February.
    17. Estelle Vincendeau & Wenming Wei & Xuefei Zhang & Cyril Planchais & Wei Yu & Hélène Lenden-Hasse & Thomas Cokelaer & Juliana Pipoli da Fonseca & Hugo Mouquet & David J. Adams & Frederick W. Alt & Step, 2022. "SHLD1 is dispensable for 53BP1-dependent V(D)J recombination but critical for productive class switch recombination," Nature Communications, Nature, vol. 13(1), pages 1-16, December.
    18. Sree Deepthi Muthukrishnan & Riki Kawaguchi & Pooja Nair & Rachna Prasad & Yue Qin & Maverick Johnson & Qing Wang & Nathan VanderVeer-Harris & Amy Pham & Alvaro G. Alvarado & Michael C. Condro & Fuyin, 2022. "P300 promotes tumor recurrence by regulating radiation-induced conversion of glioma stem cells to vascular-like cells," Nature Communications, Nature, vol. 13(1), pages 1-19, December.
    19. Chenfei Lu & Tao Kang & Junxia Zhang & Kailin Yang & Yang Liu & Kefan Song & Qiankun Lin & Deobrat Dixit & Ryan C. Gimple & Qian Zhang & Zhumei Shi & Xiao Fan & Qiulian Wu & Daqi Li & Danyang Shan & J, 2025. "Combined targeting of glioblastoma stem cells of different cellular states disrupts malignant progression," Nature Communications, Nature, vol. 16(1), pages 1-21, December.
    20. Metztli Cisneros-Aguirre & Felicia Wednesday Lopezcolorado & Linda Jillianne Tsai & Ragini Bhargava & Jeremy M. Stark, 2022. "The importance of DNAPKcs for blunt DNA end joining is magnified when XLF is weakened," Nature Communications, Nature, vol. 13(1), pages 1-17, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:natcom:v:16:y:2025:i:1:d:10.1038_s41467-025-60228-z. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    If CitEc recognized a bibliographic reference but did not link an item in RePEc to it, you can help with this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.