The histone H3-H4 tetramer is a copper reductase enzyme

Science. 2020 Jul 3;369(6499):59-64. doi: 10.1126/science.aba8740.


Eukaryotic histone H3-H4 tetramers contain a putative copper (Cu2+) binding site at the H3-H3' dimerization interface with unknown function. The coincident emergence of eukaryotes with global oxygenation, which challenged cellular copper utilization, raised the possibility that histones may function in cellular copper homeostasis. We report that the recombinant Xenopus laevis H3-H4 tetramer is an oxidoreductase enzyme that binds Cu2+ and catalyzes its reduction to Cu1+ in vitro. Loss- and gain-of-function mutations of the putative active site residues correspondingly altered copper binding and the enzymatic activity, as well as intracellular Cu1+ abundance and copper-dependent mitochondrial respiration and Sod1 function in the yeast Saccharomyces cerevisiae The histone H3-H4 tetramer, therefore, has a role other than chromatin compaction or epigenetic regulation and generates biousable Cu1+ ions in eukaryotes.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Biocatalysis
  • Catalytic Domain / genetics
  • Copper / metabolism*
  • Gain of Function Mutation
  • Histones / chemistry*
  • Histones / genetics
  • Histones / metabolism
  • Mitochondria / metabolism
  • Nuclear Proteins / metabolism
  • Oxidoreductases / chemistry*
  • Oxidoreductases / genetics
  • Oxidoreductases / metabolism
  • Protein Multimerization*
  • Recombinant Proteins / chemistry
  • Recombinant Proteins / genetics
  • Saccharomyces cerevisiae / enzymology
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae Proteins / chemistry
  • Saccharomyces cerevisiae Proteins / metabolism
  • Superoxide Dismutase-1 / chemistry
  • Transcription Factors / metabolism
  • Xenopus laevis


  • Histones
  • MAC1 protein, S cerevisiae
  • Nuclear Proteins
  • Recombinant Proteins
  • Saccharomyces cerevisiae Proteins
  • Transcription Factors
  • Copper
  • Oxidoreductases
  • Superoxide Dismutase-1
  • copper oxidase