Nuclear histones

The family of HDAC enzymes has been named after their first substrate identified, i.e., the nuclear histone proteins. Histone proteins (H2A, H2B, H3 and H4) form an octamer complex, around which the DNA helix is wrapped in order to establish a condensed chromatin structure. The acetylation status of histones is in a dynamic equilibrium governed by histone acetyl transferases (HATs), which acetylate and HDACs which are responsible for the deacetylation of histone tails (Fig. 1). Inhibition of the HDAC enzyme promotes the acetylation of nucleosome histone tails, favoring a more transcriptionally competent chromatin structure, which in turn leads to altered expression of genes involved in cellular processes such as cell prohferation, apoptosis and differentiation. Inhibition of HDAC activity results in the activation of only a limited set of pre-programmed genes microarray experiments have shown that 2% of all genes are activated by structmally different HDAC inhibitors [1-5]. In recent years, a growing number of additional nonhistone HDAC substrates have been identified, which will be discussed in more detail below. 

Hassig, C.A. and Schreiber, S.L. Nuclear histone acetylases and deacetylases and transcriptional regulation HATs off to HDACs (1997) Curr Opin Chem Biol. 1, 300-308. 

The key role of mitochondria in DNA damage-induced apoptosis is also indicated by recent findings reporting release of histone 1.2 (H1.2) from the nucleus to the cytoplasm. H1.2 in turn activates the mitochondrial apoptosis route. While all nuclear histone H1 forms are released into the cytoplasm in a p53-dependent manner after irradiation, only HI.2, but not other H1 forms, indiuxd cytochrome c release from isolated mitochondria in a Bak-dependent manner. Considering that H1 is the prime substrate for trans-poly-ADP-ribosyladon by PARP-1, detachment of HI.2 from DNA and subsequent events of the H1.2-mediated mitochondrial... 

As shown in Table 2, cAMP increased P]-ADP-ribose incorporation above control level only in the whole cell preparation. Autoradiography of SDS-polyacrylamide gel electrophoreticaUy separated proteins from this experiment showed [ P]-ADP-ribose incorporation in many cellular proteins, including proteins identifled as nuclear histones and probably ADP-ribose polymerase. 

There are at least three types of chromosomal proteins histones, protamines, and residual proteins [58-63]. It has been estimated that the nuclear histones represent 90-92% of the total protein in the chromosome. The remaining portion (8-10%) is composed of the residual protein, or non histone proteins. 

Mauritzen and Stedman (1959, 1960) found slight but definite tissue differences in the amino acid composition of nuclear histones isolated from different organs. These differences concerned only some amino acids (aspartic and glutamic acids, alanine, leucine, isoleucine, and valine). They postulate that histones may be tissue-specific proteins. The relative quantities of the same histone fractions also differ appreciably from one tissue to another. 

Bloch, D. P., Brack, S. D. Evidence for the cytoplasmic synthesis of nuclear histone during spermiogenesis in grasshopper Chortophaga viridifasdata (de Geer). J. Cell Biol. 22, 327—340 (1964). 

Bloch, D. P., Hew, H. Y. C. (2) Changes in nuclear histones during fertilization, and early embryonic development in the pulmonate snail. Helix aspersa. J. biophys. biochem. Cytol. 8, 69—81 (1960). 

Monesi, V. Autoradiographic evidence of a nuclear histone synthesis during mouse spermiogenesis in the absence of detectable quantities of nuclear ribonucleic acid. Exp. Cell Res. 36, 683—688 (1964). 

Freedman, M. L., Honig, G. R., and Rabinovitz, M. (1966). The role of newly synthesized RNA on nuclear histone synthesis by chicken immature erythrocytes. Exptl. Cell Res. 44, 263-272. 

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