Histone post-translational modifications occur, not only in the N-terminal tail domains, but also in the core domains. While modifications in the N-terminal tail function largely through the regulation of the binding of non-histone proteins to chromatin, based on their location in the nucleosome, core domain modifications may also function through distinct mechanisms involving structural alterations to the nucleosome. This article reviews the recent developments in regards to these novel histone modifications and discusses their important role in the regulation of chromatin structure.

Previous studies have shown that loss of the type B histone acetyltransferase Hat1p leads to defects in telomeric silencing in Saccharomyces cerevisiae. We used this phenotype to explore a number of functional characteristics of this enzyme. To determine whether the enzymatic activity of Hat1p is necessary for its role in telomeric silencing, a structurally conserved glutamic acid residue (Glu-255) that has been proposed to be the enzymes catalytic base was mutated. Surprisingly neither this residue nor any other acidic residues near the enzymes active site were essential for enzymatic activity. This suggests that Hat1p differs from most histone acetyltransferases in that it does not use an acidic amino acid as a catalytic base. The effects of these Hat1p mutants on enzymatic activity correlated with their effects on telomeric silencing indicating that the ability of Hat1p to acetylate substrates is important for its in vivo function. Despite its presumed role in the acetylation of newly synthesized histones in the cytoplasm, Hat1p was found to be a predominantly nuclear protein. This subcellular localization of Hat1p is important for its in vivo function because a construct that prevents its accumulation in the nucleus caused defects in telomeric silencing similar to those seen with a deletion mutant. Therefore, the presence of catalytically active Hat1p in the cytoplasm is not sufficient to support normal telomeric silencing. Hence both enzymatic activity and nuclear localization are necessary characteristics of Hat1p function in telomeric silencing.Hat1p is a member of the GNAT 2 family of histone acetyltransferases (1). This enzyme was originally identified in Saccharomyces cerevisiae but is broadly conserved throughout eukaryotes (2-8). Hat1p serves as a paradigm for type B histone acetyltransferases that were originally distinguished from type A histone acetyltransferases on the basis of a number of criteria (9). First, type B histone acetyltransferases have the ability to acetylate free histones but are inactive on nucleosomal substrates. Second, type B histone acetyltransferases are thought to be involved in the acetylation of newly synthesized histones that correlates with the process of chromatin assembly and hence are likely to function in the cytoplasm.Consistent with its designation as a type B histone acetyltransferase, Hat1p was originally isolated from yeast cytoplasmic extracts (3). In addition, Hat1p can readily acetylate free histones but has no activity with nucleosomal histones as substrate. The histone specificity of Hat1p is also consistent with its identification as a type B histone acetyltransferase as the enzyme is specific for histone H4 lysines 5 and 12 (for recombinant yeast Hat1p), which matches the evolutionarily conserved pattern of acetylation found on newly synthesized histone H4 (2, 3, 10, 11).Relative to most other histone acetyltransferases, which exist in large, multisubunit complexes, Hat1p is found in comparatively simple complexes in yeast cells (12). When isolated from t...

Pob3p is an essential component of the S. cerevisiae FACT complex (yFACT). Several lines of evidence indicate that the yFACT complex plays an important role in chromatin assembly including the observation that the pob3 Q308K allele is synthetically lethal with an allele of histone H4 that prevents the diacetylation of newly synthesized molecules. We have analyzed the genetic interactions between the Q308K allele of POB3 and mutations in all of the sites of acetylation that have been identified on newly synthesized histones. Genetic interactions were observed between POB3 and sites of acetylation on the NH2-terminal tails of H3 and H4. For histone H3, lysine residues 14 and 23 were particularly important when POB3 activity is compromised. Surprisingly, synthetic defects observed when the pob3 Q308K allele was combined with mutations of H4 lysines 5 and 12, were not phenocopied by deletion of HAT1, which encodes the enzyme that is thought to generate this pattern of acetylation on H4. Genetic interactions were also observed between POB3 and sites of acetylation found in the core domain of newly synthesized histones H3 and H4. These include synthetic lethality with an allele of H4 lysine 91 that mimics constitutive acetylation. While the mutations that alter H4 lysines 5, 12 and 91 do not affect binding to Pob3p, mutation of histone H3 lysine 56 decreases the association of histones with Pob3p. These results support the model that the yFACT complex plays a central role in chromatin assembly pathways regulated by acetylation of newly synthesized histones.