STING causes replication stress and nascent DNA degradation via SAMHD1

STING is a key innate immune adaptor, classically activated by cytosolic DNA via cGAS-cGAMP to induce type I interferon signaling. While its cytoplasmic role is well defined, recent studies reveal that STING participates in non-canonical signaling pathways and localizes at the nuclear envelope and chromatin, where its functions remain poorly understood. In Hutchinson Gilford Progeria Syndrome (HGPS), a premature aging disease caused by expression of lamin A mutant protein named progerin, STING accumulates in the nucleus and drives chronic inflammation. Here, we show that replication stress (RS) is a trigger of STING nuclear accumulation and binding to chromatin. In addition, we uncover a previously unrecognized role for nuclear STING binding to nascent DNA and promoting RS in progeria and tumor cells. Mechanistically, STING contributes to replication fork slowing and stalling by limiting dNTPs availability. In addition, STING hinders replication fork protection/stability upon stalling, by facilitating MRE11-mediated nascent DNA degradation (NDD). We also find that STING contribution to depletion of dNTPs and NDD is mediated by SAMHD1. As such, SAMHD1 knockdown phenocopies STING abrogation in progeria cells and rescues replication fork speed and stability in STING-overexpressing tumor cells. These findings define a pathological STING-SAMHD1 axis that drives RS 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. HighlightsO_LIReplication stress in human fibroblasts triggers STING nuclear accumulation and an IFN response C_LIO_LISTING upregulation and nuclear accumulation hinders replication in progeria fibroblasts and U2OS tumor cells C_LIO_LISTING-induced replication stress features fork slowing/stalling and nascent DNA degradation C_LIO_LISTING-induced fork slowing/stalling is mediated by the dNTPase SAMHD1 C_LIO_LISAMHD1-enabled MRE11 activity is responsible for STING-induced nascent DNA degradation C_LI