A toxic STING-SAMHD1 axis drives replication stress in progeria and cancer cells.

STING is an innate immune adaptor, classically activated by cytosolic DNA via cGAS-cGAMP to induce interferon signaling. Recent studies reveal that STING participates in non-canonical signaling pathways and localizes to the nucleus, where its functions remain poorly understood. In Hutchinson-Gilford Progeria Syndrome (HGPS), a premature aging disease caused by expression of the lamin-A mutant protein 'progerin', STING accumulates in the nucleus and drives chronic inflammation. Here, we show that replication stress is a trigger of STING nuclear accumulation and chromatin binding. In addition, we uncover that STING binds to nascent DNA and promotes replication stress in progeria and tumor cells. Mechanistically, STING causes replication fork slowing and stalling by limiting dNTPs availability. Upon fork stalling, STING hinders replication fork protection/stability by facilitating MRE11-mediated nascent DNA degradation (NDD). Importantly, STING's contribution to dNTP depletion and NDD is mediated by SAMHD1. Depletion of SAMHD1 phenocopies STING abrogation in reducing replication stress in progeria cells, and rescues replication fork speed and stability in STING-expressing tumor cells. These findings define a pathological STING-SAMHD1 axis that drives replication stress and genome instability in both progeria cells and tumor cells with elevated STING activity, uncovering a feedforward loop between innate immune signaling and impaired DNA replication.