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

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 (<i>Nothobranchius furzeri</i>) and demonstrate that genetic disruption of <i>cgas</i> in the A-T model partially ameliorates germline failure, hepatic senescence(definition), and cerebellar neuroinflammation. Unexpectedly, <i>cgas</i> loss also reversed cellular hallmarks of genome instability, including reduced micronuclei, improved telomere(definition) 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 <i>cgas</i> loss in an otherwise naive background exacerbates pathology and genomic instability, underscoring its essential role in normal physiology.