In our cells, 6 feet (1.8 m) of DNA gets crammed into chromosomes that fit inside a 6-µm-wide nucleus. The proteins that help pack up that genetic material are histones, which act as spools around which DNA coils. These proteins don’t just play a structural role. Through processes that unwind and re-wind these coils of DNA, histones help regulate which genes are expressed at a given time.
Now, a new study reports that these proteins also have another, more ancient gig. They can act as enzymes that reduce copper ions—which cells need for metabolic processes—from a toxic form, Cu(II), to a usable one, Cu(I). This enzymatic role may have allowed single-cell organisms to cope with a huge rise in oxygen levels on Earth. It may also have had a hand in the evolution of more complex cells, called eukaryotes, that later came became multicellular organisms.
“Our work suggests that the presence of histones was actually essential for the formation of the first eukaryotes,” says Siavash Kurdistani, a biochemist at the University of California, Los Angeles who led the study.
Scientists think that the earliest living cells used metal ions to power their biochemistry. But the sharp increase in oxygen on the planet a little over 2 billion years ago—which geologists refer to as the Great Oxidation Event—made a lot of these metals unusable because the high levels of oxygen converted them to forms that were toxic to the cells.
The histones that we carry in our eukaryotic cells descend from similar but simpler proteins in a class of ancient one-celled organisms called archaea, which existed during that oxygen jump. Unlike eukaryotes, these organisms have small genomes, and they don’t have a nucleus, suggesting that the cells didn’t need histones’ DNA-packing abilities. So Kurdistani wondered whether these ancient histones might have originally played a different role and whether that role is conserved in histones today.
Histone proteins that are present in both archaea and eukaryotes consist of a tetramer of two H3 and two H4 proteins. A decades-old study hinted that two pairs of the amino acids cysteine and histidine, located at the point where the two H3 proteins meet, might bind metal ions. Based on that study, and what Kurdistani calls a “wild guess,” he and his colleagues set out to probe whether these proteins could act as enzymes to reduce copper.
They conducted two sets of experiments. First, they mutated the amino acid sequence of a histone protein in a simple eukaryote, Saccharomyces cerevisiae, at the region where metal-binding activity had been suggested. The eukaryotic cells containing the mutant histones had lower levels of Cu(I) ions, suggesting that the histone was indeed involved in reducing copper. In another experiment, they determined that the human H3-H4 tetramer could reduce copper at a decent rate in a test tube (Science 2020, DOI: 10.1126/science.aba8740).
“They’ve shown that in isolation, [human histones] are actually quite respectable enzymes,” says Karolyn Luger, a biochemist who studies the structures of DNA and histones at the University of Colorado Boulder and was not involved in the study but did write an accompanying commentary about it. Today’s eukaryotic cells have evolved multiple other ways of keeping copper in its non-toxic Cu(I) form, but the fact that histones still seem to do so strongly suggests that it might have been their original job, she says.
“This is a big story,” says Steven Henikoff, a biologist who studies histones at the Fred Hutchinson Cancer Research Center and who was not involved in the study. Around the time of the Great Oxidation Event, eukaryotic cells also started to host mitochondria, cellular compartments that act as metabolic power sources. The fact that Cu(I) is key to mitochondrial function might mean that histones play a previously unrecognized role in cell metabolism, he says.
Indeed, Kurdistani and his colleagues are now exploring the role of histones in mitochondrial diseases.