2026-01-30 ゲーテ大学
<関連情報>
- https://aktuelles.uni-frankfurt.de/english/a-broken-dna-repair-tool-accelerates-aging/
- https://www.science.org/doi/10.1126/science.adx9445
DNA-タンパク質架橋はcGAS-STING誘導による早期老化と胚致死を促進する DNA-protein cross-links promote cGAS-STING–driven premature aging and embryonic lethality
Ines Tomaskovic, Cristian Prieto-Garcia, Maria Boskovic, Mateo Glumac, […] , and Ivan Dikic
Science Published:29 Jan 2026
DOI:https://doi.org/10.1126/science.adx9445
Editor’s summary
DNA can become trapped in harmful knots with proteins. These DNA-protein cross-links interfere with normal cell functions and, if not repaired, cause errors when cells divide. Tomaskovic et al. found that the enzyme SPRTN protects against these problems by removing cross-links. When SPRTN is missing, damaged DNA leaks into the cell’s interior, where it mistakenly triggers immune defenses. In mice, this constant immune activation led to inflammation, developmental failure, and signs of premature aging. Blocking the immune pathway reversed these effects, showing that faulty DNA repair can shorten life by provoking harmful immune responses. —Stella M. Hurtley
Structured Abstract
INTRODUCTION
DNA-protein cross-links (DPCs) are highly toxic lesions in which proteins become covalently attached to DNA, blocking essential processes such as replication and transcription. To maintain genome stability, cells rely on specialized repair mechanisms that remove DPCs. The protease SPRTN was the first enzyme identified to resolve these lesions by cleaving the protein component from DNA. Although SPRTN’s function has been well-documented during DNA replication, its role in other phases of the cell cycle remains less understood. Importantly, inherited inactivating mutations in SPRTN cause Ruijs-Aalfs progeria syndrome (RJALS), a rare disorder marked by premature aging and early-onset liver cancer. These observations suggest that unrepaired DPCs have profound effects on health, though the mechanisms linking them to aging and disease remain unclear.
RATIONALE
We hypothesized that persistent DPCs caused by SPRTN inactivation could interfere with mitosis, leading to chromosome mis-segregation, micronucleus formation, and accumulation of mislocalized DNA fragments in the cytoplasm. Such unresolved DPCs may both compromise genome integrity and activate the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) cGAS-STING innate immune pathway through recognition of cytosolic DNA and micronuclei. Given the established role of chronic inflammation in aging, we reasoned that cGAS-STING–mediated inflammatory signaling might contribute to the pathological outcomes of SPRTN deficiency, including progeroid phenotypes.
RESULTS
We found that SPRTN repairs DPCs not only during replication (S phase) but also mitosis (M phase). Inactivation of SPRTN led to the accumulation of DPCs, resulting in chromosome segregation errors and formation of micronuclei containing persistent DPCs and damaged DNA. DNA released into the cytoplasm from these defective nuclei was sensed by the cGAS-STING pathway, triggering inflammatory signaling. Consistently, SPRTN-deficient cells exhibited elevated cytoplasmic DNA and increased expression of interferon-stimulated genes, demonstrating activation of cGAS-STING by DPC-induced DNA leakage.
To explore the physiological consequences of this response, we generated a mouse model carrying a Y118C Sprtn mutation identified in RJALS. These mice accumulated unrepaired DPCs and micronuclei, showed strong innate immune activation, and phenocopied the human disorder. The animals displayed early-onset progeroid traits including reduced body size, craniofacial malformations, eye defects, lipodystrophy, kyphosis, and premature hair graying, some of which manifested during embryogenesis. Genetic or pharmacological inhibition of cGAS-STING from early development ameliorated progeroid features and rescued embryonic lethality. These findings demonstrate that innate immune activation plays a central role in the pathophysiology of unrepaired DPCs.
CONCLUSION
Our study reveals that unrepaired DPCs, including those arising in mitosis, can activate innate immune pathways with harmful consequences for development and aging. SPRTN is essential for repairing both replicative and mitotic DPCs, thereby preventing these lesions from eliciting immune responses. Inhibition of the cGAS-STING pathway rescued mice from lethal developmental defects and premature aging driven by DPC accumulation, uncovering a previously unrecognized link between DNA repair failure and immune-mediated inflammatory disease. These results establish DPCs as a class of DNA damage that promotes chronic inflammation and degenerative aging and suggest that targeting innate immune signaling could represent a therapeutic strategy for disorders caused by defective DPC repair, including RJALS.
DNA-protein cross-links drive cGAS-STING–mediated premature aging.
SPRTN depletion causes DNA-protein cross-link (DPC) accumulation, leading to defective mitosis and micronucleus formation. Micronuclei exhibit nuclear envelope assembly defects and rupture, triggering aberrant cGAS-STING activation and inflammatory gene expression. These events induce premature aging, beginning during embryonic development and persisting into adulthood. [Figure created with BioRender.com]
Abstract
DNA-protein cross-links (DPCs) are highly toxic DNA lesions that block replication and transcription, but their impact on organismal physiology is unclear. We identified a role for the metalloprotease SPRTN in preventing DPC-driven immunity and its pathological consequences. Loss of SPRTN activity during replication and mitosis lead to unresolved DNA damage, chromosome segregation errors, micronuclei formation, and cytosolic DNA release that activates the cyclic GMP-AMP synthase (cGAS)–stimulator of interferon genes (STING) pathway. In a Sprtn knock-in mouse model of Ruijs-Aalfs progeria syndrome, chronic cGas-Sting signaling caused embryonic lethality through inflammation and innate immune responses. Surviving mice displayed aging phenotypes beginning in embryogenesis, which persisted into adulthood. Genetic or pharmacological inhibition of cGas-Sting rescued embryonic lethality and alleviated progeroid phenotypes.
