Biology subjects

Teodoro-Castro, B.

Publications and source records attributed to Teodoro-Castro, B..

3 recordsLinked to original sources

bioRxiv2026

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

cell biology↗

bioRxiv2025

A non-canonical cGAS-STING pathway drives cellular and organismal aging

Accumulation of cytosolic DNA has emerged as a hallmark of aging, inducing sterile inflammation. STING (Stimulator of Interferon Genes) protein translates the sensing of cytosolic DNA by cGAS (cyclic-GMP-AMP synthase) into an inflammatory response. However, the molecular mechanisms whereby cytosolic DNA-induced cGAS-STING pathway leads to aging remain poorly understood. We show that STING does not follow the canonical pathway of activation in human fibroblasts passaged (aging) in culture, senescent fibroblasts, or progeria fibroblasts (from Hutchinson Gilford Progeria Syndrome patients). Despite cytosolic DNA buildup, features of the canonical cGAS-STING pathway like increased cGAMP production, STING phosphorylation, and STING trafficking to perinuclear compartment are not observed in progeria/senescent/aging fibroblasts. Instead, STING localizes at endoplasmic reticulum, nuclear envelope, and chromatin. Despite the non-conventional STING behavior, aging/senescent/progeria cells activate inflammatory programs such as the senescence-associated secretory phenotype (SASP) and the interferon (IFN) response, in a cGAS and STING-dependent manner, revealing a non-canonical pathway in aging. Importantly, progeria/aging/senescent cells are hindered in their ability to activate the canonical cGAS-STING pathway with synthetic DNA, compared to young cells. This deficiency is rescued by activating vitamin D receptor signaling, unveiling new mechanisms regulating the cGAS-STING pathway in aging. Significantly, in HGPS, inhibition of the non-canonical cGAS-STING pathway ameliorates cellular hallmarks of aging, reduces tissue degeneration, and extends the lifespan of progeria mice. Our study reveals that a new feature of aging is the progressively reduced ability to activate the canonical cGAS-STING pathway in response to cytosolic DNA, triggering instead a non-canonical pathway that drives senescence/aging phenotypes. Significance StatementOur study provides novel insights into the mechanisms driving sterile inflammation in aging and progeria. We reveal a previously unrecognized characteristic of aging cells: the progressive loss of ability to activate the canonical response to foreign or self-DNA at the cytoplasm. Instead, aging, senescent, and progeria cells activate inflammatory programs via a non-conventional pathway driven by cGAS and the adaptor protein STING. Importantly, pharmacological inhibition of the non-canonical cGAS-STING pathway ameliorates cellular, tissue and organismal decline in a devastating accelerated aging disease (Hutchinson Gilford Progeria Syndrome), highlighting it as a promising therapeutic target for age-related pathologies.

cell biology↗

bioRxiv2021

A-type lamins are critical for the recruitment of RPA and RAD51 to stalled replication forks to maintain fork stability

Lamins provide a nuclear scaffold for compartmentalization of genome function that is important for genome integrity. The mechanisms whereby lamins regulate genome stability remain poorly understood. Here, we demonstrate a crucial role for A-type lamins preserving the integrity of the replication fork (RF) during replication stress (RS). We find that lamins bind to nascent DNA strands, especially during RS, and ensure the recruitment of fork protective factors RPA and RAD51. These ssDNA-binding proteins, considered the first and second responders to RS respectively, play crucial roles in the stabilization, remodeling and repair of the stalled fork to ensure proper restart and genome stability. Reduced recruitment of RPA and RAD51 upon lamins depletion elicits replication fork instability (RFI) depicted by MRE11 nuclease-mediated degradation of nascent DNA, RS-induced accumulation of DNA damage, and increased sensitivity to replication inhibitors. Importantly, in contrast to cells deficient in various homology recombination repair proteins, the RFI phenotype of lamins-depleted cells is not linked to RF reversal. This suggests that the point of entry of nucleases is not the reversed fork, but regions of ssDNA generated during RS that are not protected by RPA and RAD51. Consistently, RFI in lamins-depleted cells is rescued by forced elevation of the heterotrimeric RPA complex or RAD51. These data unveil a clear involvement of structural nuclear proteins in the protection of ssDNA from the action of nucleases during RS by warranting proper recruitment of ssDNA binding proteins RPA and RAD51 to stalled RFs. In support of this model, we show physical interaction between RPA and lamins. Our study also suggests that RS is a major source of genomic instability in laminopathies and in lamins-depleted tumors.

cancer biology↗