Zinc Regulates the Copper Reductase Activity of Yeast Nucleosomes

Abstract

Histone H3 is a copper reductase enzyme that generates Cu1+ ions for intracellular copper trafficking and metalation of copper-dependent proteins. Whether this activity operates within native nucleosomes, and how it is regulated, has remained unclear. Here, we show that native yeast nucleosomes possess robust copper reductase activity that depends on the histone H3 catalytic site and is strongly influenced by zinc. Zinc acts at two levels, acutely stimulating Cu2+ reduction in vitro while also establishing a catalytically competent nucleosome state during cell growth. Consistently, impaired zinc uptake lowers cellular Cu1+ bioavailability, whereas genetically enhancing nucleosome copper reductase activity partially restores Cu1+ availability, improves growth under zinc limitation, and suppresses transcriptional signatures of disrupted zinc homeostasis. These findings reveal the nucleosome as an enzyme complex, identify zinc as a regulator of nucleosome-mediated copper reduction, and support a broader view of chromatin as a metabolic organelle linking metal availability to cellular physiology.