The histone H3-H4 tetramer is a copper reductase enzyme

Area of Science:

• Biochemistry
• Cell Biology
• Molecular Biology

Background:

• Eukaryotic histone H3-H4 tetramers possess a copper (Cu²⁺) binding site at their dimerization interface with an undefined role.
• The evolutionary emergence of eukaryotes coincided with increased atmospheric oxygen, presenting challenges for cellular copper management.

Purpose of the Study:

• To investigate the function of the histone H3-H4 tetramer's copper binding site.
• To determine if histones play a role in cellular copper homeostasis.

Main Methods:

• Recombinant Xenopus laevis H3-H4 tetramer was used to study copper binding and reduction in vitro.
• Loss- and gain-of-function mutations were introduced to analyze the effects on copper metabolism and function in Saccharomyces cerevisiae.

Main Results:

• The recombinant H3-H4 tetramer demonstrated oxidoreductase activity, catalyzing the reduction of Cu²⁺ to Cu¹⁺.
• Mutations in the putative active site altered copper binding, enzymatic activity, intracellular Cu¹⁺ levels, and copper-dependent mitochondrial respiration and Sod1 function in yeast.

Conclusions:

• Histone H3-H4 tetramers possess a novel enzymatic function beyond chromatin compaction and epigenetic regulation.
• These tetramers actively generate bioavailable Cu¹⁺ ions, contributing to cellular copper homeostasis in eukaryotes.