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 higher levels of interferon-stimulated genes.
Furthermore, to assess the physiological impact of the loss of protease and the cellular response, the scientists generated a mouse model with an RJALS-associated SPRTN mutation. They reported that the mutated animals had the physical symptoms observed with cases of the human disorder, including reduced body size, craniofacial and eye abnormalities, and premature hair graying. Some of those defects arose during embryogenesis, according to the data. The team also found that inhibiting the cGAS-STING pathway during early development rescued the mice from embryonic lethality and premature aging caused by the accumulation of DPCs.
“These results establish DPCs as a class of DNA damage that promotes chronic inflammation and degenerative aging,” alongside issues like double-strand breaks and stalled replication forks, they wrote. Furthermore, “the observation that progeroid features originate during embryogenesis and persist throughout life suggests that early development failures lay the foundation for accelerated aging.”
