📰 "STING causes replication stress and nascent DNA degradation via SAMHD1"
https://www.biorxiv.org/content/10.64898/2026.03.28.714577v1?rss=1 #Lamin
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 caused by expression of lamin A mutant protein named progerin, STING accumulates in the nucleus and drives chronic inflammation. Here, we report 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 availabilithy. In addition, STING hinders replication fork protection/stability upon stalling, by facilitating MRE11-mediated nascent DNA degradation (NDD). We also find taht 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 replication.
### Competing Interest Statement
The authors have declared no competing interest.
National Institutes of Health, https://ror.org/01cwqze88, RAG082759A, RAG076145A, R01AG058714
Glenn Foundation for Medical Research Postdoctoral Fellowship in Aging Research, PD24164
📰 "Lamin A/C as a Molecular Link Between Nuclear Organization, Chromatin Dynamics, and Tumor Progression"
https://doi.org/doi:10.3390/cells15060501https://pubmed.ncbi.nlm.nih.gov/41892292/ #Mechanics #Dynamics #Lamin
The cytoskeleton contributes to abnormal genome–lamina interactions in LMNA-deficient cardiomyocytes
Shen et al. demonstrate that LMNA reduction alters peripheral genome organization in human cardiomyocytes through cytoskeletal forces transmitted by the LI
📰 "Lamin A/C as a Molecular Link Between Nuclear Organization, Chromatin Dynamics, and Tumor Progression"
https://doi.org/doi:10.3390/cells15060501https://pubmed.ncbi.nlm.nih.gov/41892292/ #Lamin📰 "The cytoskeleton contributes to abnormal genome-lamina interactions in LMNA-deficient cardiomyocytes"
https://doi.org/doi:10.1083/jcb.202506137https://pubmed.ncbi.nlm.nih.gov/41891953/ #Cytoskeleton #Lamin📰 "A Conserved Geometric Code: Extracellular Matrix Curvature Directs Cell Migration Strategy via Nuclear Mechanosensing"
https://www.biorxiv.org/content/10.64898/2026.03.24.713851v1?rss=1 #Lamin
A Conserved Geometric Code: Extracellular Matrix Curvature Directs Cell Migration Strategy via Nuclear Mechanosensing
Cells navigate complex tissue microenvironments defined by intricate physical cues, yet how they interpret the three-dimensional geometry of the extracellular matrix (ECM) remains an open question. Current models often fail to account for the tortuous architectures found in physiological tissues. Here, we demonstrate that ECM curvature functions as a tissue-specific geometric code read by the cell nucleus. By mapping collagen architectures across cancers and tissues, we find unique curvature fingerprints preserved during metastasis. Using micro-engineered substrates, we show that high curvature imposes localized nuclear bending stress, triggering a Lamin A/C-cPLA2-Ca2+ mechanotransductive cascade. This sensor rewires the cytoskeleton from longitudinal stress fibers to a cortical actomyosin network, driving a sharp transition from fast mesenchymal migration to a slower, exploratory amoeboid phenotype. We term this "nuclear curvotaxis", establishing a physical principle linking static geometry to dynamic strategy, with implications for predicting metastatic risk, understanding immune exclusion, and designing bio-instructive scaffolds for tissue engineering.
### Competing Interest Statement
The authors have declared no competing interest.
National Natural Science Foundation of China, 12572352, 12225208, 12432015
Surface Project (Key Grant) of Chinese Medicine Education Assciation, 2024KTZ037
Technology Innovation Leading Program of Shaanxi, 2024QCY-KXJ069
Scientific Research Program Funded by Education Department of Shaanxi Provincial Government, 24JP160
📰 "A Case of Restrictive Dermopathy With Atypical Cardiac Anomalies and a Novel ZMPSTE24 Variant"
https://doi.org/doi:10.1002/ajmg.a.70149https://pubmed.ncbi.nlm.nih.gov/41877632/ #Lamin📰 "Dynamic changes in Lamin B1 and heterochromatin coincide with chromatin condensation during human erythropoiesis"
https://doi.org/doi:10.1186/s13059-026-04025-xhttps://pubmed.ncbi.nlm.nih.gov/41872884/ #Lamin
Dynamic changes in Lamin B1 and heterochromatin coincide with chromatin condensation during human erythropoiesis - Genome Biology
Background Chromatin condensation, accompanied by pronounced nuclear shrinkage, is a pivotal step in terminal erythroid differentiation and is essential for enucleation. However, the precise timing and molecular mechanisms initiating this process remain poorly understood, particularly as global transcriptional repression occurs only at the orthochromatic erythroblast stage. Results Here we perform a comprehensive analysis of three-dimensional chromatin architecture dynamics during erythropoiesis using integrative epigenomic and imaging approaches. We demonstrate that chromatin condensation begins earlier than previously recognized, initiating at the late basophilic erythroblast stage. Mechanistically, these intergenic regions were tethered to the nuclear lamina (predominantly heterochromatic) and enriched in H3K9me3, which drive large-scale chromatin compaction. Furthermore, we find that the redistribution of H3K9me3 and dynamic remodeling of Lamin B1 are critical for this structural transition, directly impacting erythroid maturation. Conclusions These findings reveal a previously unrecognized regulatory axis linking H3K9me3 and chromatin-lamina interactions, providing novel insights into the spatial and temporal control of chromatin organization during erythroid development.
📰 "First Generation Proteolysis Targeting Chimeras (PROTACs) for the Treatment of Progeria"
https://doi.org/doi:10.1002/advs.202521608https://pubmed.ncbi.nlm.nih.gov/41869760/ #Lamin📰 "Nucleus confinement within concave microcavities modulates nuclear morphology, subnuclear dynamics and mechanotransduction in human osteosarcoma cells"
https://www.biorxiv.org/content/10.64898/2026.03.20.712604v1?rss=1 #Lamin
Nucleus confinement within concave microcavities modulates nuclear morphology, subnuclear dynamics and mechanotransduction in human osteosarcoma cells
Cells dynamically integrate biochemical and mechanical signals arising from their surrounding microenvironment to regulate morphology and behavior. Mechanical cues like matrix stiffness, surface topography, and other physical perturbations modify biophysical signals. Surface topography, particularly curvature regime acts as any important mediator of mechanotransduction by coordinating cytoskeletal organization, focal adhesion dynamics, and nuclear architecture. Curvature response has been demonstrated at broader length scales and influences nucleus shape change, chromatin organization, and gene regulation, positioning the nucleus as an active mechanosensitive hub. Bone tissue consists of a curvature-rich microenvironment defined by a trabecular architecture at tissue scale and by resorption cavities such as Howship lacunae at cellular scale. While these geometries are essential for homeostasis, their role in pathological context remains poorly understood. Osteosarcoma develops within this mechanically complex multiscale architecture, but how bone-inspired curvature regulates nuclear behavior and signaling in osteosarcoma cells remains unclear. Here, we engineered three-dimensional (3D) concave hemispherical substrates that recapitulate nucleus-scale bone micro-curvature and assessed their effects on human SaOS-2 osteosarcoma cells. In comparison with flat surfaces, concave confinement resulted in pronounced nuclear rounding and softening, accompanied by Lamin A/C reorganization and increased heterochromatin compaction marked by H3K9me3. Curvature-driven nuclear remodeling selectively modulated Hippo pathway main effectors YAP/TAZ without activating NF-kB mediated canonical inflammatory responses. Furthermore, cells maintained overall viability without elevated pathological DNA damage or apoptotic signaling, suggesting an adaptive, damage-tolerant nuclear response. Overall, these findings indicate nucleus-scale curvature as a critical regulator within the bone microenvironment that governs nuclear modelling and mechanosensitive signaling in osteosarcoma cells. Incorporating physiologically relevant geometry into in vitro models establishes new insight into cancer microenvironment crosstalk and highlights nuclear interior and outer architecture as a key regulator of tumor cell behavior.
### Competing Interest Statement
The authors have declared no competing interest.
Agence Nationale de la Recherche, https://ror.org/00rbzpz17, ANR-22-CE45-0010.
Rxiv cytoskeleton
Rxiv mechanobio