Core histones variants

The lower evolutionary constraint on the sequences of CENP-A-type variants in comparison to most other core histone variants could in part reflect the very limited context in which CENP-A functions, i.e., only in centromeric chromatin associated with the kinetochore. Most other variants appear to be rather widely distributed in the chromatin, and therefore, may be involved in a greater variety of interactions and modifications that could constrain their structure during evolution. 

Zweidler, A. (1984) In Stein, G.S., Stein, J.L., and Marzluff, W.F. (eds.) Core Histone Variants of the Mouse Primary Structure and Differential Expression in Histone Genes. Wiley, New York, pp. 339-371. 

Fig. 1. Amino acid sequence of several representative homomorphous human core histone variants [12] A. Histone H2A B. Histone H2B C. Histone H3 and D. histone H4 variants. The amino acid residues are shaded with intensity proportional to the extent of identity shared among the compared sequences.

Finally, it is possible that factors affecting the individual stability of the nucleo-some (see Section 5.1.2) may also indirectly affect the folding of the chromatin fiber. The characterization of chromatin complexes consisting of core histone variants (see Section 6.1) may be very useful in this regard. 

Histones are small, basic proteins required to condense DNA into chromatin. They have been first described and named in 1884 by Albrecht Kossel. There are five main histones HI, H2A, H2B, H3 andH4. An octamer of core histones H2A, H2B, H3 andH4 is located inside a nucleosome, the central building block of chromatin, with about 150 base pairs of DNA wrapped around. The basic nature of histones, mediated by the high content of lysine and arginine residues, allows a direct interaction with the acidic phosphate back bone of DNA. The fifth histone HI is located outside at the junction between nucleosomes and is referred to as the linker histone. Besides the main histones, so-called histone variants are known, which replace core histones in certain locations like centromers. 

The similarity of the various histone fibers is probably correlated with the similarity in the distribution of the amino acids in the sequences of the four core histones and reflects their function as the skeleton or backbone of chromatin. However, from the presence of a specific pattern of interactions of the core histones and the existence of histone variants and histone postsynthetic modifications, one can anticipate modulations in the basic general pattern of histone structure. In Section V, a possible mechanism for histone microheterogeneity influencing chromatin structure is suggested. Analogous to other assembly systems, small subunit modifications may be amplified to produce major changes in the assembled superstructure. 

Luger K, Mader, AW., Richmond RK, Sargent DF, Richmond TJ (1997) Crystal structure of the nucleosome core particle at 2.8 A resolution. Nature 389 251-260 Ma Y, Jacobs SB, Jackson-Grusby L, Mastrangelo MA, Torres-Betancourt JA, Jaenisch R, Rasmussen TP (2005) DNA CpG hypomethylation induces heterochromatin reorganization involving the histone variant macroH2A. J Cell Sci 118 1607-1616... 

Nucleosomes core particles containing H2A only have 118 base pairs of DNA incorporated compared to the canonical nucleosomes protecting about 147 base pairs from micrococcal nuclease (Bao et al. 2004). These nucleosomes are more flexible in structure and might facilitate passage of RNA polymerase II. However, the function of this histone variant in mammalian cells is not fully understood. As... 

In 1978, not only were all the major classes of histone recognized, but also sequences for the major variants of each had been determined. For example, all four core histones for calf had been sequenced (see Ref. [1], Chapter 4). The existence of certain minor variant forms had been established by electrophoretic analysis as early as 1966 [46]. However, the conclusive evidence for non-allelic variants... 

The four core histones, H2A, H2B, H3, H4 and their variants, and the linker histone HI subtypes are susceptible to a wide range of post-synthetic modifications, including acetylation, phosphorylation, methylation, ubiquitination, and ADP-ribosylation (Figs. 1 and 2). In this chapter, the four latter modifications and their functions in chromatin structure and function are presented. 

Histone phosphorylation was first reported in 1966 [1,2]. The four core histones, histone variants, and HI histones are phosphorylated, with the sites of phosphorylation being found in both the amino-terminal and carboxy-terminal portions of the histones [3] (Figs. 1 and 2). Phosphorylation of the core histones has been implicated in transcription, replication, chromosome condensation, and DNA repair. 

Fig. 6. Post-translational modifications of core and linker histones. The sites of acetylation, phosphorylation, poly-ADP ribosylation, methylation, and ubiquitination are incficated by numbers that correspond to the amino acid position from the N-termini of the molecules. The nomenclature of histone HI variants is as in Fig. 3. The length of C- and N-terminal tails is in relative scale between core histones to illustrate primary structural differences between these proteins.

All of the core histones share a conserved 65-residue histone fold.27 28 The arginine-rich histones have a strongly conserved amino acid sequence, histone H4 from pea seedlings differing from that of the bovine thymus by only two amino acids. On the other hand, the lysine-rich HI is almost species-specific in its sequence. Differentiated tissues contain at least seven variant forms of histone HI including proteins designated HI0, Hit, and H5 29-31... 

Numerous additional proteins are recruited to sites of DNA damage. One of the characteristics of chromatin in the vicinity of damaged DNA is the phosphorylation of the variant core histone H2A.X at serine 139 to create the y-H2A.X isoform. Phosphorylation of H2A.X is catalyzed by ATM and ATR and forms a binding site for the protein MDCl. MDCl acts as an adapter protein that recruits the MRN complex to sites of DNA damage. Other important adapter proteins include BRCAl and p53BPl, both of which are required for optimal activation of ATM and ATR when DNA is damaged. 

The organisation of the core histones together with the HI in clusters may have evolved to enable a coordinate expression through the cell cycle. The expression of histone H5 and the intron-carrying variants H2Ap and H3.3 are separately controlled and have not been shown to be linked to the other histone genes (Sugarman ei al, 1983 Dalton ei al, 1989). 

A low-energy in vitro form of nucleosome packing was observed in nucleosome core particle crystals (Finch et al., 1977). Two variants of these crystals occurred, (a) Wavy columns of nucleosomes stacked one on top of each other with an axial repeat of 340 A were obtained upon crystallization of nucleosomes containing proteolytically cleaved histones (Finch et al., 1977). (b) Straight columns of closely packed nucleosomes, 110 A in diameter, were obtained upon crystallization of nucleosomes with intact histones (Finch and Klug, 1978). In both these structures histone-histone contacts between nucleosomes are implied. Similar face-to-face packing of nucleosomes in arcs and helical patterns was observed in the EM by Dubochet and Noll (1978). 

Strahl BD, Allis CD (2000) The language of covalent histone modifications. Nature 403 41-45 Suto RK, Clarkson MJ, Tremethick DJ, Luger K (2000) Crystal structure of a nucleosome core particle containing the variant histone H2A.Z. Nature Struct. Biol. 7 1121-1124 Swaminathan J, Baxter EM, Corces VG (2005) The role of histone H2Av variant replacement and histone H4 acetylation in the establishment of Drosophila heterochromatin. Genes Dev 19 65-76... 

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