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Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma

Oncogene volume 44, pages 1781–1792 (2025)Cite this article

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Abstract

Temozolomide (TMZ) resistance is one of the critical factors contributing to the poor prognosis of glioblastoma (GBM). As a first-line chemotherapeutic agent for GBM, TMZ exerts its cytotoxic effects through DNA alkylation. However, its therapeutic efficacy is significantly compromised by enhanced DNA damage repair (DDR) mechanisms in GBM cells. Although several DDR-targeting drugs have been developed, their clinical outcomes remain suboptimal. Post-translational modifications (PTMs) in GBM cells play a pivotal role in maintaining the genomic stability of DDR mechanisms, including methylguanine-DNA methyltransferase-mediated repair, DNA mismatch repair dysfunction, base excision repair, and double-strand break repair. This review focuses on elucidating the regulatory roles of PTMs in the intrinsic mechanisms underlying TMZ resistance in GBM. Furthermore, we explore the feasibility of enhancing TMZ-induced cytotoxicity by targeting PTM-related enzymatic to disrupt key steps in PTM-mediated DDR pathways. By integrating current preclinical insights and clinical challenges, this work highlights the potential of modulating PTM-driven networks as a novel therapeutic strategy to overcome TMZ resistance and improve treatment outcomes for GBM patients.

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Fig. 1: DNA repair mechanisms in TMZ-resistant glioblastoma.

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Funding

This work was supported by the National Natural Science Foundation of China (82203035) to Jianxiong Ji, National Natural Science Foundation of China (82403931) to Kaikai Ding, National Key Research and Development Program of China (2023YFC2510004) to Gao Chen.

Author information

Author notes

  1. These authors contributed equally: Yike Chen, Kaikai Ding, Shuyu Zheng.

Authors and Affiliations

  1. Department of Plastic Surgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Yike Chen & Chenggang Yi

  2. Department of Radiation Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China

    Kaikai Ding

  3. Department of Neurosurgery, Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China

    Shuyu Zheng, Xiaohui Xu, Haijian Wu, Fengqi Zhou, Yongjie Wang, Jinfang Xu, Chun Wang, Chenhan Ling, Jing Xu, Lin Wang, Qun Wu, Gao Chen, Jianmin Zhang & Jianxiong Ji

  4. Key Laboratory of Precise Treatment and Clinical Translational Research of Neurological Diseases, Hangzhou, Zhejiang, China

    Shuyu Zheng, Xiaohui Xu, Haijian Wu, Fengqi Zhou, Yongjie Wang, Jinfang Xu, Chun Wang, Chenhan Ling, Jing Xu, Lin Wang, Qun Wu, Gao Chen, Jianmin Zhang & Jianxiong Ji

  5. Guali Branch of the First People’s Hospital of Xiaoshan District, Hangzhou, Zhejiang, China

    Songting Gao

  6. Department of Biochemistry and Biomedicine, School of Life Sciences, University of Sussex, JMS Building, Falmer, Brighton, UK

    Georgios Giamas

  7. International Oncology Institute, The First Affiliated Hospital of Zhejiang Chinese Medical University, Oncology Department of the First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, China

    Georgios Giamas

  8. Brain Research Institute, Zhejiang University, Hangzhou, Zhejiang, China

    Jianmin Zhang

  9. MOE Frontier Science Center for Brain Science & Brain-Machine Integration Zhejiang University, Hangzhou, Zhejiang, China

    Jianmin Zhang

Authors
  1. Yike Chen
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  2. Kaikai Ding
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Contributions

YKC, KKD, and SYZ wrote and edited the manuscript. STG, and XXH produced the figures and illustrations. HJW, FQZ, YJW, JFX, CW, CHL, JX, LW, QW, GC and GG gave intellectual input, JMZ, CGY, and JXJ conceived and organized the manuscript.

Corresponding authors

Correspondence to Jianmin Zhang, Chenggang Yi or Jianxiong Ji.

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Chen, Y., Ding, K., Zheng, S. et al. Post-translational modifications in DNA damage repair: mechanisms underlying temozolomide resistance in glioblastoma. Oncogene 44, 1781–1792 (2025). https://doi.org/10.1038/s41388-025-03454-5

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