Unrepaired DNA-protein crosslinks (DPCs) – highly toxic tangles of protein and DNA –  cause a process that leads to premature aging and embryonic lethality in mice. The findings reveal a previously unrecognized link between defective DNA repair and immune-driven inflammatory disease. They also suggest that targeting innate immune signaling may offer a therapeutic strategy for human disorders like Ruijs-Aalfs progeria syndrome (RJALS), which are caused by defective DPC repair. DPCs form when proteins become covalently trapped to DNA. These harmful knots block essential cellular processes, including DNA replication and transcription. The protease SPRTN plays a critical role in maintaining genome stability by repairing DPCs during DNA replication. While its role during DNA replication is well established, its functions in other phases of the cell cycle are less understood. Moreover, inherited mutations in SPRTN are known to cause RJALS – a rare disorder marked by premature aging and early-onset liver cancer.

Through cellular analyses, Ines Tomaskovic and colleagues show that SPRTN repairs DPCs not only during DNA replication, but also during mitosis. Loss of SPRTN causes DPC accumulation, leading to chromosome segregation defects and the formation of micronuclei containing persistent DPCs and damaged DNA. DNA released from aberrant nuclei accumulates in the cytoplasm and is detected by the cGAS-STING innate immune pathway, triggering inflammatory signaling. To assess the physiological impact of this response, Tomaskovic et al. generated a mouse model carrying the RJALS-associated SPRTN mutation. The authors found that these animals accumulated unrepaired DPCs and micronuclei, showed a strong innate immune response, and exhibited key features of the human disorder, including reduced body size, craniofacial and eye abnormalities, and premature hair graying, with some defects arising during embryogenesis. Notably, inhibition of cGAS-STING from early development rescued mice from developmental lethality and premature aging caused by DPC accumulation.