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  3. Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers

Targeting thymine DNA glycosylase induces synthetic lethality in p53-deficient cancers

  • Nat Chem Biol. 2026 Jan 22. doi: 10.1038/s41589-025-02100-1.
Jia-Xin Zhou # 1,  Zhen-Yu Shao # 1,  Lin Zhang # 2,  Jian-Nan Guo # 3,  Meng Wang # 3,  Qin Xu 1 4,  Yi-Qin Wang 1,  Qing Xu 1,  Dan Zhou 5,  Sheng-Xiang Ren 6,  Yan-Hao Yu 1,  Zhi-Hao Lu 1,  Guo-Zheng Pang 5,  Yao Cao 3,  Yi-Lin Liu 3,  Bin Zhou 7,  Hong-Bin Ji 7,  Yi-Han Chen 8,  Hai-Ping Wu 9,  Guo-Liang Xu 10 11,  Liang Zhang 12,  Ya-Rui Du 13
Affiliations

Affiliations

  • 1 State Key Laboratory of Epigenetic Regulation and Intervention, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China.
  • 2 The International Peace Maternity and Child Health Hospital, School of Medicine, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, National Center for Translational Medicine, Shanghai, China.
  • 3 Cytosinlab Therapeutics Co., Ltd., Hangzhou, China.
  • 4 Krantz Family Center for Cancer Research, Massachusetts General Hospital, Department of Medicine, Harvard Medical School, Boston, MA, USA.
  • 5 Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University, Shanghai, China.
  • 6 Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China.
  • 7 State Key Laboratory of Cell Biology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai, China.
  • 8 State Key Laboratory of Cardiovascular Diseases and Department of Cardiology, Shanghai East Hospital, School of Medicine, Tongji University, Shanghai, China.
  • 9 Cytosinlab Therapeutics Co., Ltd., Hangzhou, China. [email protected].
  • 10 State Key Laboratory of Epigenetic Regulation and Intervention, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • 11 Shanghai Key Laboratory of Medical Epigenetics, Institutes of Biomedical Sciences, Chinese Academy of Medical Sciences (RU069) and Zhongshan-Xuhui Hospital, Medical College of Fudan University, Shanghai, China. [email protected].
  • 12 The International Peace Maternity and Child Health Hospital, School of Medicine, School of Chemistry and Chemical Engineering, Zhangjiang Institute for Advanced Study, Shanghai Jiao Tong University, National Center for Translational Medicine, Shanghai, China. [email protected].
  • 13 State Key Laboratory of Epigenetic Regulation and Intervention, Shanghai Key Laboratory of Molecular Andrology, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 41571914 DOI: 10.1038/s41589-025-02100-1
Abstract

Thymine DNA glycosylase (TDG) is a multifaceted protein involved in base-excision repair, DNA demethylation and transcriptional regulation, with key roles in embryonic development and tumorigenesis. However, the mechanisms underlying its role in Cancer progression and the therapeutic applications targeting TDG remain largely unknown. Here we demonstrate that targeting TDG induces synthetic lethality in p53-deficient cancers. We developed C-271, a first-in-class, small-molecule inhibitor that covalently binds to TDG, disrupting its DNA-binding capability. C-271 exhibits potent therapeutic efficacy in suppressing p53-deficient tumors. Mechanistically, TDG and p53 redundantly promote the transcription of DHX9, an RNA helicase that resolves double-stranded RNA (dsRNA). TDG inhibition in p53-deficient Cancer cells leads to DHX9 downregulation and, thus, aberrant dsRNA accumulation, which activates the RIG-I/MDA5-MAVS sensing pathway, resulting in tumor suppression and enhanced antitumor immunity. These findings highlight the synthetic lethality between TDG and p53, positioning TDG inhibition as a promising therapeutic strategy for p53-deficient cancers.

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