Nucleosome code

Fig. 3.18 Nucleosome core particle (NCP)-polyamide co-crystal structures (PDB codes 1M18 and 1M19). (Top) Partial structure, viewed down the superhelical axis. Base pairs 58-145 (shown in white) and associated proteins (H3, blue H4, green H2A, yellow H2B, red) are shown for each complex. Superhelix locations (SHLs) are labeled as each major...

Not all the cellular DNA is in the nucleus some is found in the mitochondria. In addition, mitochondria contain RNA as well as several enzymes used for protein synthesis. Interestingly, mitochond-rial RNA and DNA bear a closer resemblance to the nucleic acid of bacterial cells than they do to animal cells. For example, the rather small DNA molecule of the mitochondrion is circular and does not form nucleosomes. Its information is contained in approximately 16,500 nucleotides that func-tion in the synthesis of two ribosomal and 22 transfer RNAs (tRNAs). In addition, mitochondrial DNA codes for the synthesis of 13 proteins, all components of the respiratory chain and the oxidative phosphorylation system. Still, mitochondrial DNA does not contain sufficient information for the synthesis of all mitochondrial proteins most are coded by nuclear genes. Most mitochondrial proteins are synthesized in the cytosol from nuclear-derived messenger RNAs (mRNAs) and then transported into the mito-chondria, where they contribute to both the structural and the functional elements of this organelle. Because mitochondria are inherited cytoplasmically, an individual does not necessarily receive mitochondrial nucleic acid equally from each parent. In fact, mito-chondria are inherited maternally. 

Ito T (2003) Nucleosome assembly and remodehng. Curr Top Microbiol Immunol 274 1-22 Ito T, Tyler JK, Kadonaga JT (1997) Chromatin assembly factors a dual function in nucleosome formation and mobilization Genes Cells 2(10) 593-600 Ivanovska I, Khandan T, Ito T, Orr-Weaver TL (2005) A histone code in meiosis the histone kinase, NHK-1, is required for proper chromosomal architecture in Drosophila oocytes. Genes Dev 19(21) 2571-2582... 

In the sections that follow, we are going to describe a few representative examples of how histone variability (histone variants and their post-translational modifications) can affect nucleosome stability and folding. This data supports the notion that while some of this variability may be exclusively used to provide an informational code [121,123,165] it can also have important implications for structural aspects involved in the highly dynamic nature of the chromatin fiber. 

The Still limited struetural information on this intriguing post-translational modilieation seems to suggest that at least in the case of uH2A its most important role may be merely informational. Indeed, it has been suggested that histone ubiquitination could label specific chromatin domains [409 11] and as such could be a component of the histone code [121,123,165]. The structural results obtained so far with uH2A nucleosomes and nucleosome arrays clearly support this notion. 

In this cooperative binding event, the Rcol-PHD finger is primarily responsible for providing affinity for nucleosomes, while the Eafi chromodomain contributes specificity for the methylated H3K36 mark [59, 60]. These examples demonstrate how multiple domains can cooperate to read a histone code with high fidelity and enhanced affinity. 

Histones within transcriptionally active chromatin and heterochromatin also differ in their patterns of covalent modification. The core histones of nucleosome particles (H2A, H2B, H3, H4 see Fig. 24-27) are modified by irreversible methylation of Lys residues, phosphorylation of Ser or Thr residues, acetylation (see below), or attachment of ubiquitin (see Fig. 27-41). Each of the core histones has two distinct structural domains. A central domain is involved in histone-histone interaction and the wrapping of DNA around the nucleosome. A second, lysine-rich amino-terminal domain is generally positioned near the exterior of the assembled nucleosome particle the covalent modifications occur at specific residues concentrated in this amino-terminal domain. The patterns of modification have led some researchers to propose the existence of a histone code, in which modification patterns are recognized by enzymes that alter the structure of chromatin. Modifications associated with transcriptional activation would be recognized by enzymes that make the chromatin more accessible to the transcription machinery. 

E. Segal, Y. Fondufe-Mittendorf, L. Chen, A Thastrom, Y. Field, I. K. More, J-P. Z. Wang, J. Widom, A Genomic Code for Nucleosome Positioning, Nature 442 (2006) 772. 

Histones are basic proteins that are made up by a globular domain and an N-terminal tail that protrudes from the nucleosome. Nucleosomes form the basic unit of chromatin and are made up by a complex of DNA wrapped around an octamer of histones formed by pairs of the histones H2A, H2B, H3, and H4 (45,46) (Fig. 1). Post-translational modification of the core histone tails by methylation, acetylation, phosphorylation, ubiquitina-tion, or sumoylation can alter the structure of the nucleosomes and thus alter gene expression. These post-translational modifications determine the structure and pattern of chromatin condensation and determine the histone code that drives gene transcriptional regulation (47,48). Below are briefly described the factors determining the histone acetylation and methylation. 

---