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The secret double life of histone H3 as a copper reductase enzyme

July 02, 2020

In a study that takes another look at histones' origins, researchers report these proteins, known for DNA-packing, may have evolutionary roots in early life in helping to maintain the use of metals like copper - fundamental for biological processes, but which became toxic to eukaryotes as they adapted to global oxygenation. Histone proteins are highly basic proteins ubiquitous across all forms of eukaryotic life. Like spools, they form the structures around which DNA is wound. Without histones, life's exceedingly long genomic molecules wouldn't be able to be fit inside tiny cell nuclei as chromosomes. The presence of simple histones in archaea - the ancestors of all complex cellular life - suggests ancient evolutionary roots. However, their function in these forms of life isn't well understood. Using a host of approaches ranging from in vitro biochemistry to in vivo genetic and molecular analysis, Narsis Attar and colleagues discovered a previously unknown function of the histone H3-H4 tetramer. Attar et al. identified that the H3-H4 tetramer also serves as an oxidoreductase enzyme for copper, an element essential to all life. However, in nature, copper most commonly occurs in a form toxic to oxygen-utilizing organisms. The newly found reductase activity of H3-H4 makes this harmful copper oxidation state safe for use inside cells. The results suggest histones may have originally evolved in anerobic life as a way to adapt to oxygenated environments, rather than for DNA compaction. In a related Perspective, Johannes Rudolph and Karolin Luger regard the study's findings as "potentially paradigm-shifting," particularly in respect to histone evolution and subsequent adoption in DNA compaction. "Perhaps the original role of histone proteins was to protect against oxygen toxicity in response to the increase in oxygen concentrations that allowed for the evolution of eukaryotes and multicellular organisms," write Rudolph and Luger, noting that further characterization of histone function from archaeal organisms is needed to better understand their non-genomic roles.
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American Association for the Advancement of Science

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