A dual role for cGAS in shaping cellular and organismal responses to genomic instability.

Abstract

Mutations in DNA damage repair (DDR) genes lead to genomic instability, driving a range of degenerative syndromes. In addition to promoting mutation accumulation, unrepaired DNA damage can leak into the cytosol and activate innate immune-sensing pathways, particularly the cGAS-STING axis. However, the extent to which cGAS causally contributes to organismal pathology in DDR syndromes in vivo remains unresolved. Here, we genetically model ataxia telangiectasia (A-T) and Bloom syndrome in the short-lived turquoise killifish (Nothobranchius furzeri) and demonstrate that genetic disruption of cgas in the A-T model partially ameliorates germline failure, hepatic senescence, and cerebellar neuroinflammation. Unexpectedly, cgas loss also reversed cellular hallmarks of genome instability, including reduced micronuclei, improved telomere integrity, and restored H3K9me3-marked heterochromatin landscape, consistent with STING-independent nuclear functions of cGAS that influence DNA repair and chromatin. Together, these data identify cGAS as a context-dependent amplifier of DDR pathology acting through canonical inflammatory signaling and noncanonical nuclear mechanisms that shape genome stability. Accordingly, our findings support pharmacological cGAS inhibition as a potential strategy for DDR syndromes in settings of chronic DNA damage while highlighting that cgas loss in an otherwise naive background exacerbates pathology and genomic instability, underscoring its essential role in normal physiology.