The secret concert of histone enzymes may have helped drive eukaryotic evolution

In our cells, 6 feet (1.8 m) of DNA clusters on chromosomes that fit inside a 6 µm-wide nucleus. The proteins that help pack that genetic material are histones, which act as spools around which DNA is wound. These proteins not only play a structural role. Through processes that unroll and rewind these coils of DNA, histones help regulate which genes are expressed at any given time.

Now, a new study reports that these proteins also have another, older concert. They can act as enzymes that reduce copper ions, which cells need for metabolic processes, from a toxic form, Cu (II), to a usable form, Cu (I). This enzymatic function may have allowed single-celled organisms to cope with a large increase in oxygen levels on Earth. It may also have influenced the evolution of more complex cells, called eukaryotes, which later developed into multicellular organisms.

“Our work suggests that the presence of histones was really 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 first living cells used metal ions to boost their biochemistry. But the sharp rise in oxygen on the planet just over 2 billion years ago, which geologists refer to as the Great Oxidation Event, rendered many of these metals useless because high levels of oxygen turned them into forms that were toxic to cells. .

The histones we carry in our eukaryotic cells descend from similar but simpler proteins in a class of ancient single-celled organisms called archaea, which existed during that oxygen jump. Unlike eukaryotes, these organisms have small genomes and no nuclei, suggesting that cells did not need the DNA packaging capabilities of histones. Then Kurdistani wondered if these ancient histones could have originally played a different role and if that role is preserved in the histones today.

The 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 amino acids cysteine ​​and histidine, located at the point where the two H3 proteins bind, could bind metal ions. Based on that study, and what Kurdistani calls a “crazy guess,” he and his colleagues set out to investigate 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 into a simple eukaryote, Saccharomyces cerevisiae, in the region where metal binding activity was suggested. Eukaryotic cells containing the mutant histones had lower levels of Cu (I) ions, suggesting that the histone was actually involved in copper reduction. In another experiment, they determined that human H3-H4 tetramer could reduce copper at a decent rate in a test tube (Science 2020, DOI: 10.1126 / science.aba8740).

“They have shown that in isolation, [human histones] they’re actually pretty respectable enzymes, “says Karolyn Luger, a biochemist who studies DNA and histone structures at the University of Colorado Boulder and was not involved in the study, but wrote a comment about it. Today’s eukaryotic cells have He developed many other ways to keep copper in its non-toxic Cu (I) form, but the fact that histones still seem to do so suggests that it might have been his original work, he says.

“This is a great 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 began to harbor mitochondria, cellular compartments that act as sources of metabolic energy. The fact that Cu (I) is key to mitochondrial function could mean that histones play a previously unrecognized role in cellular metabolism, he says.

In fact, Kurdistani and his colleagues are now exploring the role of histones in mitochondrial diseases.