Data from a new study in mice connects unrepaired DNA-protein crosslinks (DPCs), highly toxic tangles of protein and DNA, to inflammation-linked premature aging and embryonic lethality in mice. The findings suggest that targeting innate immune signaling may be a viable therapeutic strategy for conditions caused by defective DPC repair, such as Ruijs-Aalfs progeria syndrome (RJALS) and Cockayne syndrome. Details of the work are provided in a new Science paper titled “DNA-protein cross-links promote cGAS-STING-driven premature aging and embryonic lethality.” DNA-protein crosslinks form when proteins become covalently trapped to DNA and form harmful knots that block essential cellular processes such as replication and transcription. Typically, the SPRTN protease helps with repairing DPCs during replication, which is critical for ensuring genome stability. Inherited mutations in SPRTN are known to cause RJALS, a rare-disorder marked by premature aging and early-onset liver cancer. The scientists suspected that inactivating SPRTN would cause DPCs to persist through replication and interfere with mitosis. Accumulation of DPCs would lead to defects in chromosome segregation and the formation of micronuclei containing DPCs and damaged DNA fragments in the cytoplasm. The damaged DNA would then be detected by the cGAS-STING innate immune pathway, triggering the kind of inflammatory signaling that causes the progeria phenotype. Using a range of tools, including biochemical assays and proximity approaches, the scientists showed that SPRTN is responsible for repairing DPCs during replication and mitosis. Cells with the protease inactivated accumulated unrepaired DPCs and micronuclei, and they had a strong innate immune response, as evidenced by…
