Gene Regulation: Histones, HDACs, PARPs, Ubiquitination & Sumoylation

Ubiquitination & Sumoylation C e l l C y c l e & D N A T r a n s a c t i o n s In eukaryotes, the several meters long genomic DNA needs to be packed into chromosomes with a diameter of only several hundred micrometers. This is achieved through an elaborated scheme of packaging that starts with the formation of nucleosomes from DNA winding around an octamer core of histones H2A/H2B/H3/H4, followed by linking the core with H1 and packing into chromatin, and leading finally through undefined hierarchy steps to the packed chromosome. Once thought of as static, non-participating structural elements, it is now clear that histones are integral and dynamic components of the machinery responsible for regulating gene expression. The core histones contain a central histone fold domain, which is flanked by Nand C-terminal tails. These tails, which protrude from the surface of the chromatin polymer and are protease sensitive, comprise 25-30% of the mass of individual histones, thus providing an exposed surface for potential interactions with other proteins. Histone tails are the targets of several forms of covalent modification including acetylation, methylation, ubiquitination, ADPribosylation and phosphorylation. These modifications play a central role in regulating gene expression. In addition to the core histones a number of histone variants have been identified. Histones are divided into five classes: the linker histones H1 and the core histones H2A, H2B, H3 and H4. The H1 class is subdivided into 8 subtypes H1.0-H1.5, H1T and H1X. More variants have been described. Of special interest are three H2A variants: H2AX, which i s phosphorylated at Ser (four residues from the C-terminus) in response to the introduction of DNA double-strand breaks, H2AZ, which appears to alter nucleosome stability, and macroH2A, which appears to be enriched on the inactive mammalian X chromosome (see Fig.1). Also, recent data suggest that histones may be able to distinguish between healthy and malignant cells, since many tumor cells expose abnormal structures on their cell membrane, which are bound by histones, leading to destabilization of the membrane structure and ultimately to cell death. Histone H1 has been shown to suppress tumor growth of leukemia cells in vitro, ex vivo and in animal models. In contrast to radiation and chemotherapy, histone H1 is non-toxic for normal cells. Histone H1.2 possesses strong cytochrome c-releasing activity and is released into the cytoplasm from the nucleus in response to DNA double-strand breaks, thus helps to prevent genome instability and cancer. Histones have also been shown to have antibacterial effects and might play an important role in innate immunity.