RPA1 Protects DNA damage induced PANoptosis in limb development (PRJCA032160)

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 identified that DNA damage response factors were up-regulated in proliferation mesenchymal stem cells. Conditional knockout of Rpa1, the representative DNA damage response factors, in mice resulted in the near-total absence of forelimbs and severely underdeveloped hindlimbs, characterized by the complete loss of major limb bones. Mechanistically, Rpa1 deletion led to extensive DNA damage and activated the cGAS-STING pathway, driving Zbp1 expression. ZBP1 became full activated upon binding to Z-DNA resulting from Rpa1 deletion, triggering mesenchymal stem cell death through PANoptosis. Our study reveals RPA1 as a vital protector of genomic stability during limb development and underscore ZBP1-dependent PANoptosis as a key pathway for eliminating cells with excessive DNA damage during embryonic development.