2. Academic Validation
  3. ZBP1 senses spliceosome stress through Z-RNA:DNA hybrid recognition

ZBP1 senses spliceosome stress through Z-RNA:DNA hybrid recognition

  • Mol Cell. 2025 May 1;85(9):1790-1805.e7. doi: 10.1016/j.molcel.2025.04.004.
Jianfeng He 1,  Yongyi Zhu 1,  Zichao Tian 1,  Mengqin Liu 2,  Anmin Gao 3,  Wangmi Fu 3,  Fei Lu 1,  Yutong Sun 1,  Yajun Guo 3,  Rongqing Pan 4,  Yuchen Ji 1,  Jianxiang Chen 5,  Huasong Lu 6,  Juan Lin 4,  Xingguo Liang 7,  Chun Kim 8,  Chun Zhou 9,  Huipeng Jiao 10
Affiliations

Affiliations

  • 1 Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Department of Neonatal Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China.
  • 2 State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299 Sansha Road, Qingdao 266404, China.
  • 3 School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China.
  • 4 Research Unit of Cellular Stress of Chinese Academy of Medical Sciences, Cancer Research Center of Xiamen University, School of Medicine, Xiamen University, Xiamen 361102, China.
  • 5 School of Pharmacy and Department of Hepatology, the Affiliated Hospital of Hangzhou Normal University, Hangzhou Normal University, Hangzhou 311121, China.
  • 6 Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China.
  • 7 State Key Laboratory of Marine Food Processing & Safety Control, College of Food Science and Engineering, Ocean University of China, No. 1299 Sansha Road, Qingdao 266404, China. Electronic address: liangxg@ouc.edu.cn.
  • 8 Department of Medicinal and Life Sciences, Hanyang University (ERICA Campus), Ansan 15588, Republic of Korea. Electronic address: chunkim@hanyang.ac.kr.
  • 9 School of Public Health, Zhejiang University School of Medicine, Hangzhou 310058, China. Electronic address: chunzhou@zju.edu.cn.
  • 10 Zhejiang Key Laboratory of Molecular Cancer Biology, Life Sciences Institute, Zhejiang University, Hangzhou 310058, China; Department of Neonatal Surgery, Children's Hospital, Zhejiang University School of Medicine, National Clinical Research Center for Child Health, Hangzhou 310052, China. Electronic address: hjiao@zju.edu.cn.
PMID: 40267921 DOI: 10.1016/j.molcel.2025.04.004
Abstract

Z-DNA-binding protein 1 (ZBP1; also known as DAI or DLM-1) regulates cell death and inflammation by sensing left-handed double-helical nucleic acids, including Z-RNA and Z-DNA. However, the physiological conditions that generate Z-form nucleic acids (Z-NAs) and activate ZBP1-dependent signaling pathways remain largely elusive. In this study, we developed a probe, Zα-mFc, that specifically detected both Z-DNA and Z-RNA. Utilizing this probe, we discovered that inhibiting spliceosome causes nuclear accumulation of Z-RNA:DNA hybrids, which are sensed by ZBP1 via its Zα domains, triggering Apoptosis and Necroptosis in mammalian cells. Furthermore, we solved crystal structures of the human or mouse Zα1 domain complexed with a 6-bp RNA:DNA hybrid, revealing that the RNA:DNA hybrid adopts a left-handed conformation. Our findings demonstrate that the spliceosome acts as a checkpoint preventing accumulation of Z-RNA:DNA hybrids, which potentially function as endogenous ligands activating ZBP1-dependent cell death pathways.

Keywords

Z-RNA:DNA; cell death; spliceosome inhibition.

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