Yin Qi, Peng Shuanglin, Zhang Zhong, Jiang Shuang, Li Xuan, Huang Denghao, Li Yang, Zhou Jian, Xiao Jingang, Ye Ling, Yin Yuxin, Yuan Quan
State Key Laboratory of Oral Diseases & National Center for Stomatology and National Clinical Research Center for Oral Diseases, West China Hospital of Stomatology, Sichuan University, Chengdu 610041, Sichuan, China.
Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China.
Sci Adv. 2025 Aug 22;11(34):eadw2756. doi: 10.1126/sciadv.adw2756. Epub 2025 Aug 20.
Extensive cell proliferation during embryogenesis often compromises genome integrity, increasing the risk of developmental defects. However, the mechanisms that safeguard genome integrity during this process remain poorly understood. Using early limb development as a model, we identify that DNA damage response factors are up-regulated in proliferating mesenchymal stem cells. Conditional knockout of , a representative DNA damage response factor, in early limb bud mesenchyme results in the near-total absence of forelimbs and severely underdeveloped hindlimbs. Mechanistically, deletion leads to extensive DNA damage and activates the cGAS-STING pathway, driving transcription of . deletion also leads to accumulation of Z-DNA bound by ZBP1, triggering the full activation of ZBP1 and subsequent mesenchymal stem cell death through PANoptosis. Our study reveals RPA1 as a vital protector of genomic stability during limb development and underscores ZBP1-dependent PANoptosis as a key pathway for eliminating cells with excessive DNA damage during embryonic development.
胚胎发育过程中广泛的细胞增殖常常会损害基因组完整性，增加发育缺陷的风险。然而，在此过程中保护基因组完整性的机制仍知之甚少。以早期肢体发育为模型，我们发现DNA损伤反应因子在增殖的间充质干细胞中上调。在早期肢芽间充质中条件性敲除一种代表性的DNA损伤反应因子，导致前肢几乎完全缺失，后肢严重发育不全。从机制上讲，该因子的缺失会导致广泛的DNA损伤并激活cGAS-STING通路，驱动相关基因的转录。该因子的缺失还会导致ZBP1结合的Z-DNA积累，触发ZBP1的完全激活以及随后通过PANoptosis导致间充质干细胞死亡。我们的研究揭示了RPA1是肢体发育过程中基因组稳定性的重要保护者，并强调ZBP1依赖性PANoptosis是胚胎发育过程中消除具有过多DNA损伤细胞的关键途径。
