Tongji University Cancer Center, Shanghai Tenth People's Hospital, School of Medicine, Tongji University, 200072, Shanghai, China.
Department of Biochemistry and Molecular Biology, School of Medicine, Tongji University, 200331, Shanghai, China.
Cell Death Dis. 2024 Oct 27;15(10):779. doi: 10.1038/s41419-024-07175-7.
Excessive DNA damage triggers various types of programmed cell death (PCD), yet the regulatory mechanism of DNA damage-induced cell death is not fully understood. Here, we report that PANoptosis, a coordinated PCD pathway, including pyroptosis, apoptosis and necroptosis, is activated by DNA damage. The Z-DNA binding protein 1 (ZBP1) is the apical sensor of PANoptosis and essential for PANoptosome assembly in response to DNA damage. We find endogenous retroviruses (ERVs) are activated by DNA damage and act as ligands for ZBP1 to trigger PANoptosis. By using ZBP1 knock-out and knock-in mice disrupting ZBP1 nucleic acid-binding activity, we demonstrate that ZBP1-mediated PANoptosis contributes to the toxic effects of chemotherapeutic drugs, which is dependent on ZBP1 nucleic acid-binding activity. We found that ZBP1 expression is downregulated in tumor tissue. Furthermore, in colorectal cancer patients, dsRNA is induced by chemotherapy and sensed by ZBP1 in normal colonic tissues, suggesting ZBP1-mediated PANoptosis is activated by chemotherapy in normal tissues. Our findings indicate that ZBP1-mediated PANoptosis is activated by DNA damage and contributes to the toxic side effects of DNA-damage-based chemotherapy. These data suggest that ZBP1 could be a promising therapeutic target to alleviate chemotherapy-related side effects.
过量的 DNA 损伤会触发各种类型的程序性细胞死亡（PCD），但 DNA 损伤诱导细胞死亡的调控机制尚未完全阐明。在这里，我们报告 PANoptosis（一种包括细胞焦亡、细胞凋亡和细胞坏死在内的协调的 PCD 途径）被 DNA 损伤激活。Z-DNA 结合蛋白 1（ZBP1）是 PANoptosis 的顶端传感器，是响应 DNA 损伤组装 PANoptosome 所必需的。我们发现内源性逆转录病毒（ERVs）被 DNA 损伤激活，并作为 ZBP1 的配体触发 PANoptosis。通过使用 ZBP1 敲除和敲入小鼠破坏 ZBP1 的核酸结合活性，我们证明 ZBP1 介导的 PANoptosis 有助于化疗药物的毒性作用，这取决于 ZBP1 的核酸结合活性。我们发现 ZBP1 在肿瘤组织中的表达下调。此外，在结直肠癌患者中，dsRNA 由化疗诱导，并在正常结肠组织中被 ZBP1 感知，这表明 ZBP1 介导的 PANoptosis 在正常组织中被化疗激活。我们的研究结果表明，ZBP1 介导的 PANoptosis 是由 DNA 损伤激活的，并有助于基于 DNA 损伤的化疗的毒性副作用。这些数据表明，ZBP1 可能是一个有前途的治疗靶点，以减轻化疗相关的副作用。
