Histone H3 cysteine 110 enhances iron metabolism and modulates replicative life span in Saccharomyces cerevisiae

The discovery of histone H3 copper reductase activity provides a novel metabolic framework for understanding the functions of core histone residues, which, unlike N-terminal residues, have remained largely unexplored. We previously demonstrated that histone H3 cysteine 110 (H3C110) contributes to cupric (Cu²⁺) ion binding and its reduction to the cuprous (Cu¹⁺) form. However, this residue is absent in Saccharomyces cerevisiae, raising questions about its evolutionary and functional significance. Here, we report that H3C110 has been lost in many fungal lineages despite near-universal conservation across eukaryotes. Introduction of H3C110 into S. cerevisiae increased intracellular Cu¹⁺ levels and ameliorated the iron homeostasis defects caused by inactivation of the Cup1 metallothionein or glutathione depletion. Enhanced histone copper reductase activity also extended replicative life span under oxidative growth conditions but reduced it under fermentative conditions. Our findings suggest that a trade-off between histone copper reductase activity, iron metabolism, and life span may underlie the loss or retention of H3C110 across eukaryotes.