Histone protection

Attack of non-histone-protected nucleic acids in mitochondria, induction of apoptosis... 

Figure 36-2. Model for the structure of the nucleosome, in which DNA is wrapped around the surface of a flat protein cylinder consisting of two each of histones H2A, H2B, H3, and H4 that form the histone octamer. The 146 base pairs of DNA, consisting of 1.75 superhelical turns, are in contact with the histone octamer. This protects the DNA from digestion by a nuclease. The position of histone HI, when it is present, is indicated by the dashed outline at the bottom of the figure.

The histone core protects the DNA bound to the nucleosome from digestion by pan-creatic deoxyribonuclease (DNase) I or micrococcal nuclease. Nucleases, however, will cleave the linker DNA that connects the nucleosome subunits to one another. 

Meneghini MD, Wu M, Madhani HD (2003) Conserved histone variant H2A.Z protects euchromatin from the ectopic spread of silent heterochromatin. Cell 112 725-736 Mermoud JE, Costanzi C, Pehrson JR, Brockdorff N (1999) Histone macroH2A1.2 relocates to the inactive X chromosome after initiation and propagation of X-inactivation. J Cell Biol 147 1399-1408... 

The genetic information of eukaryotic cells is propagated in the form of chromosomal DNA. Besides the nucleic acid component, chromosomes contain architectural proteins as stoichiometric components, which are involved in the protective compaction of the fragile DNA double strands. Together, the DNA and proteins form a nucleoprotein structure called chromatin. The fundamental repeating unit of chromatin is the nucleosome core particle. It consists of about 147 base pairs of DNA wrapped around a histone octamer of a (H3/H4)2 tetramer and two (H2A-H2B) heterodimers. One molecule of the linker histone HI (or H5) binds the linker DNA region between two nucleosome core particles (Bates and Thomas 1981). 

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... 

HD In Drosophila models of Huntington s disease, the HDAC inhibitors SAHA and sodium butyrate arrest the progressive neuronal degeneration and lethality (Steffan et al, 2001). SAHA and sodium butyrate have also been demonstrated to extend survival, ameliorate motor deficits and delay characteristic neuropathology in the mouse Huntington s disease model, R6/2 (Ferrante et al, 2003 Hockly et al, 2003). In NaBu-treated animals, animals displayed enhanced acetylation status of histones and pro-survival transcription factors like Spl and reduction in several neuropatho-logical hallmarks like striatal neuronal atrophy (Ferrante et al, 2003). Consistent with the idea that HDAC inhibition relieves transcriptional repression and that protection is downstream of mutant htt, neither SAHA nor sodium butyrate decreased mutant htt expression or aggregates (Ferrante et al, 2003 Hockly et al, 2003). 

The weakly immunogenic protamine sulfate USP (1) condenses DNA to form a toroid structure of super-coiled DNA about 50 nm in diameter (2). The DNA in this form or in the preformed LPDI complex cannot be displaced from the protamine by polycations such as spermidine and histones or by other nucleic acids like genomic DNA (2). DNA in this toroid structure is transcriptionally inactive and this conformation allows for protection of DNA from enzymatic degradation by nucleases and other environmental assaults such as mechanical stress (1,2). After the liposome surrounds the toroid, the resulting homogenous LPDI nanoparticles are slightly less than... 

A poly-A tail is attached to the 3 end. In this process, an endonuclease cuts the molecule on the 3 side of the sequence AAUAAA (poly-A addition signal), then poly-A polymerase adds the poly-A tail (about 200 As) to the new 3 end. The poly-A tail protects the message against rapid degradation and aids in its transport to the cytoplasm. A few mRNAs (for example, histone mRNAs) have no poly-A tails. 

An, W., van Holde, K., and Zlatanova, J. (1998) The non-histone chromatin protein HMGl protects linker DNA on the side opposite to that protected by linker histones. J. Biol. Chem. 273, 26289-26291. 

Several lines of evidence indicate that CENP-A replaces conventional H3 in the nucleosome. Biochemical studies showed that CENP-A co-sediments with nucleo-some core particles [7] and a genetic analysis indicates an interaction between Cse4p, the CENP-A of Saccharomyces cerevisiae, and H4 [16,17]. A recent study with CENP-A purified from HeLa cells or expressed in bacteria showed that it can substitute for conventional H3 in nucleosome reconstitution [18]. Reconstituted CENP-A-containing nucleosomes appear to contain the other core histones in appropriate stoichiometry. However, they did not strongly protect 146 bp of core DNA from micrococcal nuclease, suggesting that CENP-A may significantly alter some aspects of the core nucleosome structure. 

Relationships between histone methylation and DNA methylation and histone acetyation and DNA methylation have been reported [191,314,315], A similar relationship may exist between poly(ADP ribosylated) HI and DNA methylation. Inhibition of poly(ADP-ribose) polymerase with 3-aminobenzamide increases the susceptibility of L929 mouse fibroblast nuclei to be methylated by endogenous DNA methyltransferases [316,317], Further, there is evidence that poly(ADP ribosylation) protects CpG islands located at the 5 end of housekeeping genes from methylation [318], Future studies will likely reveal an interesting dynamic relationship between histone methylation, histone acetylation, and histone poly(ADP-ribosylation). 

ADP-ribosylation has also been implicated as a proteolytic antagonist during embryonic development [231]. Following fertilization in sea urchin, sperm-specific histones are degraded by the sperm-histone-selective (SpH) protease and subsequently replaced by cleavage stage histone variants. During this process, the maternal replacement histones are protected from proteolysis by ADP-ribosylation. 

One of the very early research tools that were used to study the nucleosomal state of active genes were the nucleases, DNase I and Micrococcal nuclease. With the development of protocols for the isolation of nuclei from cells, it was possible to add these reagents to probe the accessibility of DNA. DNase I makes single nicks in double stranded DNA and when the DNA is associated with histones within the nucleosome, the DNA is extensively protected. Those nicks that are observed are found to occur only after extensive digestion and are limited to the outside surface of the DNA in 10 base increments [7,8]. Weintraub and Groudine in 1976 [9] first used this nuclease and observed that when nuclei from chicken erythrocytes were treated with DNase I, the active /1-globin gene was preferentially... 

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