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  • The stable association of Hat complexes with histones H

    2022-01-17

    The stable association of Hat1 complexes with histones H3 and H4 raises a number of interesting issues. The first is the question of how Hat1 remains stably associated with histones H3 and H4. While the simple answer is that Hat1 remains bound to histones because of its association with histone chaperones, the real answer may be more complicated. For example, while Hat1 must interact with the histone H4 tail to acetylate lysines 5 and 12, it is not known whether the Hat1 active site remains associated with the H4 tail after modification. Acetylation of lysine 5 and/or 12 may result in a reorganization of the complex such that the histones become primarily associated with the histone chaperone subunits. This scenario is supported by the observation that the Hat1–Hat2(Rbap46) core complex may have multiple modes of interaction with histone H4. In isolation, the Rbap46/48 Adenine sulfate do not bind to the H4 NH2-terminal tail domain but are capable of interacting with the first α-helix [65], [83]. However, in the context of the Hat1 core complex, Hat1 and Hat2(Rbap46) can stably interact with a peptide encoding the H4 NH2-terminal tail domain and this domain is required for the interaction of the complex with the full-length histone [50], [113]. Therefore, the components of the Hat1 core complex interact with histone H4 through multiple mechanisms and it will be important to determine whether the mode of interaction between the Hat1 core complex and histones is static or whether the interaction is dynamic depending on factors such as modification state of the histones or sub-cellular localization of the complex. There are a number of alternative explanations (that are non-mutually exclusive) for the stable association of Hat1 with histones. A related model is that, rather than protecting lysines 5 and 12 from deacetylation, the binding of Hat1 to histone H4 could prevent the inappropriate modification of other residues. H4 lysine 12 is positioned in the active site of Hat1, in part, through the alignment of H4 lysines 8 and 16 with acidic patches on Hat1 [114]. In fact, the presence of positive charge at positions 8 and 16 is important for the catalytic activity of Hat1 [115], [116]. If the H4 NH2-terminal tail remains bound in the active site of Hat1 following its acetylation, lysines 8 and 16 would be inaccessible to nuclear type A HATs. Given the important role of histone H4 lysine 16 acetylation in transcriptionally active chromatin, the Hat1 complexes may play an important role in maintaining proper patterns of epigenetic inheritance by preventing the acetylation of this residue until after chromatin is assembled [117]. Another scenario to explain the association of Hat1 complexes with histones H3 and H4 relates to the presence of multiple histone chaperones in these complexes. For example, the NuB4 complex, which contains both Hat2p(Rbap46) and Hif1p(NASP), also interacts with Asf1p [27], [61], [104]. It appears likely that all of these histone chaperones are binding to the histones simultaneously as the histones play an important role in mediating the interactions between in these multi-chaperone complexes [61], [97]. One of the primary functions of histone chaperones, which are negatively charged proteins, has been proposed to be the shielding of the highly concentrated positive charge of the histones to prevent inappropriate interactions [118]. However, structural studies of histone chaperones indicate that they make relatively limited contact with the histones that would not shield a significant fraction of the histones positive charge [119]. Therefore, it may be necessary for multiple chaperones to associate with histones H3 and H4 during the process of histone deposition. In fact, Hat1p itself is an acidic protein with an isoelectric point of 5.1. Therefore, in addition to its catalytic activity, Hat1 may also contribute to the histone chaperone activity of its associated complexes.