Science 369, 59–64 (2020)

The eukaryotic histone H3–H4 tetramer contains conserved residues at the dimerization interface reminiscent of copper-binding sites in other proteins, but the functional implications of this site have been a mystery. Now, Attar et al. have demonstrated that in addition to binding copper ions, the H3–H4 tetramer also has an active role in maintaining cellular metal homeostasis. In vitro, purified Xenopus laevis H3–H4 tetramers exhibit cupric reductase activity (reducing Cu2+ to Cu+), involving two key residues in histone H3, Cys110 and His113. Wild-type yeast H3 lacks the Cys110 residue but retains cupric reductase activity, which is increased by installation of an A110C mutation. In yeast cells, substitution of His113 with alanine was lethal, while substitution with asparagine or tyrosine caused growth defects, impaired mitochondrial respiration, and decreased superoxide dismutase activity due to decreased Cu+ abundance. The characterization of an additional function for the histone tetramer identifies a new player in eukaryotic metal homeostasis and hints at the activities of related archaeal proteins that lack a known epigenetic role.