In their latest work, a team of researchers led by Ivan Dikic shows that the DPC-repair enzyme SPRTN works not only during DNA replication but also in mitosis to clear these DNA lesions. When SPRTN is impaired, damaged DNA leaks into the cell’s cytoplasm and activates the cGAS-STING innate immune pathway, leading to chronic inflammation.

DNA–protein crosslinks (DPCs) are bulky DNA lesions that stall essential processes like replication and transcription. The metalloprotease SPRTN normally removes these harmful knots, keeping chromosomes error-free during cell division. Mutations in the SPRTN gene cause Ruijs-Aalfs syndrome, a rare genetic disorder characterised by progeroid features – including premature ageing – and early-onset hepatocellular carcinoma.

In their latest work, a team of researchers led by Ivan Dikic shows that the DPC-repair enzyme SPRTN works not only during DNA replication but also in mitosis to clear these DNA lesions. When SPRTN is impaired, damaged DNA leaks into the cell’s cytoplasm and activates the cGAS-STING innate immune pathway, leading to chronic inflammation. In a mouse model mirroring human Ruijs-Aalfs progeria syndrome, this immune overdrive causes partial embryonic lethality, premature ageing and progeroid features that begin in the embryo and persist into adulthood. However, genetic or pharmacological inhibition of the immune pathway cGAS-STING (e.g., STING inhibitor H-151) improves survival and alleviates ageing and progeroid traits, directly tying chronic innate immune activation to the consequences of unresolved DPCs.