Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1191224 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR31570916_1.fastq.gz | Fastqsanger.gz | |||
| SRR31570916_2.fastq.gz | Fastqsanger.gz | |||
| SRR31570917_1.fastq.gz | Fastqsanger.gz | |||
| SRR31570917_2.fastq.gz | Fastqsanger.gz | |||
| SRR31570918_1.fastq.gz | Fastqsanger.gz |
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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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