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
    ---><---

    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.

    We have no bibliographic references for this item. You can help adding them by using 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.