DNA-Protein Crosslinks Promote cGAS-STING-driven Premature Aging and Embryonic Lethality

DNA-protein crosslinks (DPCs) are severe DNA lesions that disrupt replication, transcription, and genome stability. However, their role in development and aging remains poorly understood. Here, we show that impaired SPRTN function, a metalloprotease essential for DPC repair during replication and mitosis, leads to DNA damage, mitotic abnormalities, and activation of the immune system. Notably, micronuclei formed upon SPRTN deficiency frequently contain DPCs, exhibit nuclear envelope rupture, and accumulate unrepaired DNA, thereby facilitating activation of the cGAS-STING pathway. Using a Sprtn knock-in mouse model of Ruijs Aalfs progeria syndrome, we demonstrate that chronic cGas-Sting activation drives inflammation, innate immune responses, and embryonic lethality. Surviving mice display a continuum of aging phenotypes from embryogenesis into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescues embryonic viability and ameliorates progeroid features, linking DPC-induced innate immune activation to lifespan defects. Our findings uncover a previously unrecognized role for DPCs in coupling early developmental failure to premature aging.

DNA-蛋白质交联（DNA-protein crosslinks, DPCs）是一类严重的DNA损伤，可干扰DNA复制、转录过程并破坏基因组稳定性。然而，其在发育与衰老进程中的作用仍未被充分阐明。本研究发现，SPRTN——一种在复制与有丝分裂阶段负责DPC修复的关键金属蛋白酶——功能受损时，会引发DNA损伤、有丝分裂异常，并激活机体免疫系统。值得注意的是，SPRTN缺陷诱导形成的微核通常携带有DPCs，会出现核膜破裂现象，并积累未修复的DNA，进而促进cGAS-STING通路的激活。我们借助鲁伊斯-阿尔夫斯早衰综合征（Ruijs Aalfs progeria syndrome）的Sprtn敲入小鼠模型，证实慢性cGAS-STING通路激活会驱动炎症反应、先天免疫应答，并导致胚胎致死。存活小鼠则呈现出从胚胎发育至成年阶段的一系列衰老表型。通过遗传或药理学手段抑制cGAS-STING通路，可挽救胚胎存活率并改善早衰相关特征，从而将DPC诱导的先天免疫激活与寿命缺陷建立关联。本研究的发现揭示了DPCs此前未被认知的功能：将早期发育失败与过早衰老联系起来。