Genome-wide CRISPR screen reveals genetic modifiers of Ca 2+ -mediated cell death.

Ca 2+ is a fundamental determinant of survival in living cells. Excessive intracellular Ca 2+ causes cellular toxicity and death but the genetic pathways contributing to Ca 2+ induced cell death are incompletely understood. Here, we performed genome-wide CRISPR knock-out screening in human cells challenged with the Ca 2+ ionophore ionomycin and identified genes and pathways essential for cell death after Ca 2+ 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 2+ entry (SOCE), very long-chain fatty acid synthesis, and SWItch/Sucrose Non-Fermentable (SWI/SNF) pathways provided marked protection against Ca 2+ toxicity. These results reveal pathways previously unknown to mediate Ca 2+ -induced cell death and provide a resource for the development of pharmacotherapies against the sequelae of Ca 2+ overload in disease.