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  • A second site of histone core domain acetylation that that


    A second site of histone core domain acetylation that that has been observed on newly synthesized histones is histone H4 lysine 91 [34]. H4 lysine 91 lies along the interface between the H3/H4 tetramer and the H2A/H2B dimers. In fact, H4 lysine 91 normally forms a salt bridge with an aspartic androgen receptor inhibitor residue in histone H2B [35]. Hence, neutralization of the positive charge of H4 lysine 91 may function to destabilize tetramer–dimer interactions and, thus, regulate the process of histone octamer assembly. Histone H4 lysine 91 is also a highly conserved modification that has been observed in human, bovine and yeast cells [34], [36], [37]. It is not known whether histone H4 lysine 91 acetylation is specifically found on newly synthesized histones. However, the fact that this modification was observed on molecules associated with a nuclear Hat1p-containing complex suggests that this may be the case. In addition, consistent with a role for H4 lysine 91 acetylation in chromatin assembly, genetic analysis of these mutations indicates that this modification functions in common pathways with histone chaperones Asf1 and CAF-1 [34].
    Despite its exceptional degree of evolutionary conservation, a specific function for the diacetylation of newly synthesized histone H4 on lysines 5 and 12 has not been identified. In fact, although the presence of this modification pattern is closely correlated with histone deposition, a number of studies suggest that this acetylation plays, at most, a minor role in chromatin assembly. For example, genetic studies in yeast involving mutants in which histone H4 lysines 5 and 12 are changed to arginine showed that the absence of this acetylation pattern had no effect on chromatin assembly and caused no defects in cell proliferation or viability [38], [39], [40]. In addition, replication-coupled chromatin assembly mediated by the CAF-1 complex was shown to function normally in the complete absence of the NH2-terminal tails of histones H3 and H4 [41]. However, a recent study in Physarum polycephalum suggests that histone H4 lysine 5/12 acetylation promotes chromatin assembly in this organism. Thiriet and colleagues demonstrated that exogenously added histone proteins could be imported into the nucleus and assembled into chromatin. Taking advantage of this interesting model system, it was found that introducing histone H4 proteins with lysine to arginine substitutions at positions 5 and 12 dramatically reduced nuclear import. Importantly, changing these lysine residues to glutamine (thought to mimic constitutive acetylation) increased the rate of nuclear import [42]. A similar result was also recently reported using an in vitro nuclear translocation assay in HeLa cells where an H4 tail-EYFP fusion protein was more readily transported when lysines 5 and 12 were changed to glutamine to mimic constitutive acetylation [43]. These important results identify a specific step in the chromatin assembly pathway, namely histone import into the nucleus, that may be regulated by the diacetylation of newly synthesized histone H4. The biochemical characterization of histone acetyltransferase activities from a variety of organisms suggested that the enzyme responsible for the acetylation of new histone H4 molecules was present in the cytoplasm [44], [45], [46], [47], [48], [49]. A histone acetyltransferase specific for free H4 was first purified to homogeneity from S. cerevisiae cytoplasmic extracts [50]. The catalytic subunit of this enzyme was named Hat1p. This enzyme displayed an absolute specificity for free histones relative to nucleosomal substrates and modified histone H4 lysine 12 (the recombinant form of the enzyme acetylated both H4 lysines 5 and 12) [50], [51]. Similar activities isolated from other organisms also targeted free histone H4 on lysines 5 and 12 [52], [53], [54], [55], [56]. While deletion of the HAT1 gene in yeast had no impact on cell proliferation or viability (similar to what is seen with the H4 K5,12R mutation), subsequent genetic analyses were also consistent with a role for HAT1 in the acetylation of newly synthesized histone H4 [50], [51]. For example, the telomeric silencing defect observed in the absence of yeast Hat1p could be phenocopied by a mutation that altered histone H4 lysine 12 to arginine (mimicking a constitutively deacetylated state) [57]. In addition, the loss of HAT1 led to a decrease in the abundance of histone H4 acetylated at lysine 12 in chromatin localized near a DNA double strand break [58].