RPA1 protects DNA damage-induced PANoptosis in limb development.

ABSTRACT: 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 Rpa1, a representative DNA damage response factor, in early limb bud mesenchyme results in the near-total absence of forelimbs and severely underdeveloped hindlimbs. Mechanistically, Rpa1 deletion leads to extensive DNA damage and activates the cGAS-STING pathway, driving transcription of Zbp1. Rpa1 deletion also leads to accumulation of Z-DNA bound by ZBP1, triggerin

SUBMITTER: Yin Q 

PROVIDER: S-EPMC12366678 | biostudies-literature | 2025 Aug

REPOSITORIES: biostudies-literature