Abstract 2297 Histones and Copper: A common thread from the origin of eukaryotes to human disease

Histones are considered to serve mainly to package large amounts of eukaryotic DNA into the confines of the nucleus and function in regulating gene expression and essentially all other processes based on DNA. However, ancestral histones were present in organisms with small genomes, no nucleus, and little ability for epigenetic regulation, suggesting that histones may have an additional, unknown function that might have served as the original impetus for their evolution. Inspired by the geochemical events surrounding the appearance of the first eukaryotic cell, we have indeed discovered a novel function for histone is an oxidoreductase enzyme with copper reductase activity, catalysing reduction of Cu2+ to Cu1+. Our data indicate that the catalytic site forming at the interface of the apposing histone H3 proteins within the nucleosome. The histones' electrochemistry predicts a previously unrecognized biological principle that not only influences cellular copper homeostasis but also governs chromatin structure and function. I will present our ongoing investigation into mechanisms of copper reduction by histone H3 and the nucleosome, the effects on cellular copper-dependent activities, and implications for eukaryogenesis as well as human disease.