Rcn1, the fission yeast homolog of human <scp>DSCR1</scp>, regulates arsenite tolerance independently from calcineurin

<jats:title>Abstract</jats:title><jats:p>Calcineurin (CN) is a conserved Ca<jats:sup>2+</jats:sup>/calmodulin‐dependent phosphoprotein phosphatase that plays a key role in Ca<jats:sup>2+</jats:sup> signaling. Regulator of calcineurin 1 (RCAN1), also known as Down syndrome critical region gene 1 (DSCR1), interacts with calcineurin and inhibits calcineurin‐dependent signaling in various organisms. Ppb1, the fission yeast calcineurin regulates Cl<jats:sup>−</jats:sup>‐homeostasis, and Ppb1 deletion induces MgCl<jats:sub>2</jats:sub> hypersensitivity. Here, we characterize the conserved and novel roles of the fission yeast RCAN1 homolog <jats:italic>rcn1</jats:italic><jats:sup>+</jats:sup>. Consistent with its role as an endogenous calcineurin inhibitor, Rcn1 overproduction reproduced the calcineurin‐null phenotypes, including MgCl<jats:sub>2</jats:sub> hypersensitivity and inhibition of calcineurin signaling upon extracellular Ca<jats:sup>2+</jats:sup> stimuli as evaluated by the nuclear translocation and transcriptional activation of the calcineurin substrate Prz1. Notably, overexpression of <jats:italic>rcn1</jats:italic><jats:sup>+</jats:sup> causes hypersensitivity to arsenite, whereas calcineurin deletion induces arsenite tolerance, showing a phenotypic discrepancy between Rcn1 overexpression and calcineurin deletion. Importantly, although Rcn1 deletion induces modest sensitivities to arsenite and MgCl<jats:sub>2</jats:sub> in wild‐type cells, the arsenite tolerance, but not MgCl<jats:sub>2</jats:sub> sensitivity, associated with Ppb1 deletion was markedly suppressed by Rcn1 deletion. Collectively, our findings reveal a previously unrecognized functional collaboration between Rcn1 and calcineurin, wherein Rcn1 not only negatively regulates calcineurin in the Cl<jats:sup>−</jats:sup> homeostasis, but also Rcn1 mediates calcineurin signaling to modulate arsenite cytotoxicity.</jats:p>