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

ABSTRACT: 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.

INSTRUMENT(S):

ORGANISM(S): Homo Sapiens (human) Mus Musculus (mouse)

TISSUE(S): Embryo, Lung, Liver

SUBMITTER: Thorsten Mosler

LAB HEAD: Ivan Dikic

PROVIDER: PXD051378 | Pride | 2025-09-30

REPOSITORIES: Pride

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			Action	DRS
	20211028_QEP1_PBE_KM_TM_Collab_Sprtn_WT_rep1_1.raw	Raw
	20211028_QEP1_PBE_KM_TM_Collab_Sprtn_WT_rep1_2.raw	Raw
	20211028_QEP1_PBE_KM_TM_Collab_Sprtn_WT_rep1_3.raw	Raw
	20211028_QEP1_PBE_KM_TM_Collab_Sprtn_WT_rep1_4.raw	Raw
	20211028_QEP1_PBE_KM_TM_Collab_Sprtn_WT_rep2_1.raw	Raw

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

Project description: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.

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Project description:Biallelic mutations in the SPRTN gene cause an autosomal recessive progeroid disease known as Ruijs–Aalfs syndrome. Patients with Ruijs–Aalfs syndrome display symptoms of premature ageing and typically develop hepatocellular carcinoma during adolescence. To study the functional role of this protein, we generated knock-in mice (Sprtn Y118C/Y118C) that largely recapitulate the Ruijs–Aalfs phenotype. These mice harbour the equivalent of the Y117C missense mutation described in Ruijs–Aalfs patients. SPRTN has recently been implicated in DNA repair, specifically in the resolution of DNA–protein crosslinks (DPCs), which facilitates replisome bypass and allows translesion synthesis across DPC adducts. Understanding this DNA repair pathway is of paramount importance, as cells lacking SPRTN are not viable, and DNA–protein lesions can be induced by UV light, ionizing radiation, or normal cellular metabolism. Moreover, a broad spectrum of chemotherapeutic drugs induces protein–DNA crosslinking. In our study, we compared the bulk transcriptome of Sprtn Y118C/Y118C and wild-type mice using RNA extracted from liver tissue.

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