Genome-wide CRISPR screen reveals genetic modifiers of Ca -mediated cell death.

Ca is a fundamental determinant of survival in living cells. Excessive intracellular Ca causes cellular toxicity and death but the genetic pathways contributing to Ca induced cell death are incompletely understood. Here, we performed genome-wide CRISPR knock-out screening in human cells challenged with the Ca ionophore ionomycin and identified genes and pathways essential for cell death after Ca overload. We discovered 115 protective gene knockouts, 82 of which are non-essential genes and 21 of which belong to the druggable genome. Notably, members of store operated Ca entry (SOCE), very long-chain fatty acid synthesis, and SWItch/Sucrose Non-Fermentable (SWI/SNF) pathways provided marked protection against Ca toxicity. These results reveal pathways previously unknown to mediate Ca -induced cell death and provide a resource for the development of pharmacotherapies against the sequelae of Ca overload in disease.