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The eukaryotic histones H2A and H3: From chromatin compaction to copper homeostasis


In eukaryotes, genome size varies disproportionately relative to nuclear size such that larger genomes are generally more compact than smaller genomes. We found that the histone H2A N-terminal domain (NTD) and the histone H2B C-terminal domain have co-evolved with genome size, and that the co-evolving residues contribute to the differential chromatin compaction in organisms as diverse as the budding yeast and humans. Interestingly, histones appear to predate eukaryotes and evolved from archaeal histone-like proteins. The structural simplicity of the ancestral histones raises doubts as to whether they participated in the types of chromatin regulatory functions histones perform today. We therefore asked whether histones performed a different function in the early eukaryotes. In the nucleosome structure, the interface region of the two histone H3 proteins forms a potential transition metal coordination site. Interestingly, the appearance of eukaryotes roughly coincided with the accumulation of oxygen, which led to the oxidation of essential transition metals like copper, and challenged cells to maintain metal homeostasis. Could histones, through a copper coordination site at the H3-H3’ interface, have provided a mechanism for maintaining the reduced Cu(I) ions to support copper-dependent processes? We show that in the budding yeast, genetic perturbation of the putative metal coordination site indeed disrupts mitochondrial respiration and superoxide dismutase function in a manner recoverable by provision of excess copper, but not other metals. These phenotypes are not explained by a deficiency in cellular copper accumulation, nor by gene expression perturbation, but are recapitulated by disruption of cellular redox state. Together, these findings suggest that histones maintain Cu(I) levels. Indeed, the histone H3-H4 tetramer assembled in vitro from recombinant histones exhibits copper reductase activity, catalyzing the conversion of Cu(II) to Cu(I). This unprecedented enzymatic function is altered by mutation of histidine and cysteine residues in the putative metal coordination region. We propose that eukaryotic chromatin is an oxidoreductase enzyme, which provides biousable copper for cellular processes. As the emergence of eukaryotes coincided with increased oxidation and therefore decreased biousability of essential metals, the enzymatic function of histones could have facilitated eukaryogenesis.

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