UCLA

Histones have long been known for their functions in packaging the eukaryotic genome and in regulating DNA-based processes. These functions are dependent on physical and chemical properties of histones constructing the nucleosome, the basic structural unit for packaging DNA. The packaging of DNA into chromatin limits DNA accessibility for processes such as transcription and DNA replication, putting the nucleosome in a position to govern and fine-tune these processes. The influence on DNA metabolic processes can be mediated through alterations in nucleosome composition and positioning as well as covalent modification of histones. Variations in nucleosome structure and stability achieved by the use of non-canonical histone variants can lead to changes in DNA wrapping and accessibility. Similarly, covalent modifications of histone N-terminal or core domains can lead to structural changes for the nucleosome and the chromatin fiber. Covalent modification of histone tails also contributes to recruitment and anchoring of protein complexes required for transcription, DNA repair and replication. Changes in histone modifications and

mutations in the enzymes adding and removing them are implicated in a wide-range of pathologies including cancer (discussed in chapters II, III and IV). Histone modifications are dynamically regulated, which makes them suitable for integration of environmental and cellular cues with gene expression. While histone modifications locally participate in orchestrating transcription, global changes in histone modifications can have profound effects on cellular physiology and metabolism. In fact, alterations in cellular levels of histone modifications are observed in diseases such as cancer and can be responsive to changes in physiologic state of the cell like intracellular pH. In addition to the well-recognized structural elements of histones, a less well-known feature of these ancient proteins is their potential metal binding capabilities. Since metals such as copper and iron are required for a variety of important functions, a potential ability of histones to affect cellular metal homeostasis would greatly increase their influence on cellular functions. Indeed we have recently discovered the function of one such metal binding site at the nucleosome core within the H3 dimerization interface in regulating copper homeostasis. Investigating the role of this region of the nucleosome in metal biology revealed an unprecedented molecular function of the nucleosome as an oxidoreductase enzyme, capable of catalyzing the reduction of Cu2+ to its biousable form Cu1+. This remarkable enzymatic activity significantly affects copper- dependent activities including mitochondrial respiration and Sod1 function, with a profound impact on the molecular biology of eukaryotes and potentially their evolutionary origin. The importance of copper for various physiological and pathological states in humans further underscores the broad implications of copper reductase activity of the nucleosome. These discoveries mark a new frontier into chromatin biology and a function of histones which may have deemed these proteins suitable participants in the emergence of eukaryotes on Earth (discussed in chapters V and VI).