The cGAS-STING pathway is an in vivo modifier of genomic instability syndromes
Abstract
Mutations in genes involved in DNA damage repair (DDR) often lead to premature aging syndromes.
While recent evidence suggests that inflammation, alongside mutation accumulation and cell death,
may drive disease phenotypes, its precise contribution to in vivo pathophysiology remains unclear. Here,
by modeling Ataxia Telangiectasia (A-T) and Bloom Syndrome in the African turquoise killifish (N.
furzeri), we replicate key phenotypes of DDR syndromes, including infertility, cytoplasmic DNA
fragments, and reduced lifespan. The link between DDR defects and inflammation is attributed to the
activation of the cGAS-STING pathway and interferon signaling by cytoplasmic DNA. Accordingly,
mutating cGAS partially rescues germline defects and senescence in A-T fish. Double mutants also
display reversal of telomere abnormalities and suppression of transposable elements, underscoring
cGAS's non-canonical role as a DDR inhibitor. Our findings emphasize the role of interferon signaling
in A-T pathology and identify the cGAS-STING pathway as a potential therapeutic target for genomic
instability syndromes.
Here, we leverage the turquoise killifish (Nothobranchius furzeri) as an experimental platform
to identify functional modifiers of genomic instability. The killifish has recently emerged as a promising
genetic model for aging, owing to a naturally compressed lifespan (~6-10-fold shorter than mice and
zebrafish, respectively35), and the availability of state-of-the-art genome editing tools36–43 75 . These
features have enabled the identification of novel vertebrate longevity mechanisms (through the
AMP/AMPK pathway or via germline manipulations41,42,44 77 ), and the rapid modeling of human agerelated syndromes (e.g. telomere syndrome36 78 )
