Our research focuses on uncovering previously unrecognized functions of the endoplasmic reticulum Ca²⁺ sensor STIM1 in genome stability and cellular homeostasis. One major line of investigation examines the role of STIM1 in the DNA damage response (DDR). DNA damage represents a constant challenge for cell viability and the faithful transmission of genetic information, requiring tightly regulated repair mechanisms. We have demonstrated that STIM1 contributes to protection against endogenous DNA damage, replicative stress, and interstrand crosslinks (ICLs). Notably, STIM1 contains a nuclear localization signal that enables its translocation to the nucleus, where its association with chromatin increases in response to the ICL-inducing agent mitomycin C. Cells lacking STIM1 exhibit elevated basal DNA damage, increased replicative stress, and heightened sensitivity to ICLs, revealing a novel nuclear function for an ER-resident protein and expanding current understanding of the molecular networks involved in DNA repair (Sanchez-Lopez et al., 2014).