The cGAS-STING pathway is an in-vivo modifier of genomic instability syndromes

To functionally explore the relationship between genomic instability and aging, we developed genetic models for DNA repair disorders in the naturally short-lived African turquoise killifish. Specifically, we mutated the Ataxia Telangiectasia (ATM) and the Bloom Syndrome (BLM) genes.

Both ATM and BLM are autosomal recessive syndromes, which are characterized by overlapping and distinct aging-related phenotypes. We show that these models replicate human disease phenotypes, including infertility, short stature, reduced lifespan, cytoplasmic DNA fragments, and activated interferon signaling. Finally, we demonstrated that mutating cGAS, a sensor of dsDNA fragments, which is upstream to interferon, rescues specific degenerative phenotypes in ATM fish.