The nuclear lamina is more than a passive scaffold; its mechanical state can directly influence signaling complexes that guard genome integrity. We hypothesize that accumulation of farnesylated prelamin A during physiological aging increases nuclear envelope stiffness, which alters the tension transmitted through LINC complexes to the cytoskeleton{Prelamin A accumulation}. It's possible that stiffened lamina also perturbs nucleocytoplasmic transport, compounding genome instability. This mechanical imbalance reduces the ability of ATM kinase to be recruited to sites of DNA damage that lie within lamina‑associated domains (LADs), even when CK2α is not sequestered{CK2 sequestrationLAD‑ATM}. Consequently, DNA double‑strand breaks persist, R‑loops accumulate, and senescence is accelerated, mirroring the phenotype seen in progerin‑expressing cells but arising from a distinct mechano‑transduction route{DSBsR-loopssenescence}.

To test this, we will measure nuclear membrane stiffness using atomic force microscopy on fibroblasts from young donors, aged donors, and HGPS patients, correlating stiffness with the amount of farnesylated prelamin A (Western blot) and ZMPSTE24 activity (fluorogenic assay) {Prelamin A accumulation}. We will then quantify ATM recruitment to laser‑induced micro‑irradiation stripes within LADs (identified by lamin B1 DamID) and outside LADs, expecting a stiffness‑dependent delay specifically in LAD regions. Rescue experiments will express a non‑farnesylated prelamin A mutant (C661S) or treat cells with the farnesyltransferase inhibitor lonafarnib to reduce membrane tension; we predict that lowering stiffness restores ATM kinetics and reduces γH2AX foci without altering CK2α localization. Finally, we will assess whether inducing controlled nuclear envelope ruptures (via transient expression of SUN1‑KASH1 dominant‑negative) exacerbates the repair defect in stiff nuclei, linking our hypothesis to the observed chromothripsis phenotype{Nuclear envelope ruptures}.

If nuclear stiffening directly impairs LINC‑mediated ATM signaling, then manipulating lamina mechanics should uncouple prelamin A accumulation from DDR failure, providing a mechanistic bridge between the CK2‑centric model and larger‑scale nuclear architecture dysregulation.