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    • Another property shared between Hat p and Rtt

    2021-10-15

    Another property shared between Hat1p and Rtt109p is a transient or substoichiometric interaction with Asf1p. Asf1p is necessary for the acetylation of histone H3 lysine 56 by Rtt109p. However, they do not appear to form a stable complex [22], [24], [27], [84], [90]. Surprisingly, the original type A HAT, Gcn5p, has also been implicated in the acetylation of the NH2-terminal tail of newly synthesized histone H3 [10], [86], [91]. Gcn5p has been shown to exist in a number of high molecular weight complexes that are very different from the simple HAT/histone chaperone structure of the Hat1 and Rtt109 complexes [62], [92], [93]. However, Gcn5p was identified as the catalytic subunit of enzyme activity that specifically acetylated non-nucleosomal histone H3 [94]. This complex did not appear to be related to the previously characterized Gcn5p-containing complexes. Therefore, it remains to be determined whether Gcn5p also associates with a histone chaperone to function in the acetylation of newly synthesized histone H3.
    Nuclear HAT1-containing complexes The core Hat1–Hat2(Rbap46/48) complex was originally purified from cytoplasmic extracts [50]. However, subsequent analyses indicated that Hat1 is actually a predominantly nuclear enzyme [95], [96], [97]. When in the nuclear compartment, this core Hat1 complex interacts with a number of other factors. The nature of these interactions provides important clues to the functional role of Hat1. The most abundant form of nuclear Hat1p in yeast is the NuB4 complex (Nuclear type B HAT specific for H4). In addition to Hat1p and Hat2p, this complex also contains Hif1p. Importantly, Hif1p appears to be present in this complex at roughly stoichiometric levels with Hat1p and Hat2p [96], [97]. Hif1p is a member of the N1 family of histone chaperones and specifically interacts with histones H3 and H4. Hif1p can also participate in the deposition of histones onto DNA suggesting that Hat1p may be directly involved in the ER 27319 maleate assembly process [96]. While Hif1p is clearly a component of the NuB4 complex, both genetic and biochemical data indicate that Hif1p also has functions in chromatin assembly that are independent of its association with Hat1p and Hat2p [97], [98]. As is the case for the core Hat1 complex, the NuB4 complex also appears to be evolutionarily conserved. This was first suggested by experiments involving the affinity purification of epitope tagged versions of human histones H3.1 and H3.3. For both histone H3 variants, not only the core Hat1 complex components, Hat1 and Rbap46/48, were found to co-purify but also the human homolog of Hif1p, known as NASP (nuclear autoantigenic sperm protein) co-purified, as well [99]. While these results did not definitively determine whether Hat1 was physically associated with NASP, a more detailed study has recently used an epitope-tagged NASP to demonstrate that it interacts with Hat1 and Rbap46 in human cells [61]. Curiously, purification of a nuclear Hat1 complex from Xenopus laevis did not detect the co-purification of N1 itself. Rather, in addition to the X. laevis Rbap46, a 14-3-3 protein was found to be a component of the nuclear Hat1 complex [64]. The function of the 14-3-3 protein/Hat1 interaction is not known but 14-3-3 proteins have been shown to directly interact with histone NH2-terminal tail domains in a modification specific manner to mediate the interaction of those histones with other HATs [100], [101]. While the NuB4 complex was originally isolated from yeast nuclear extracts, recent evidence from both yeast and human model systems suggests that interactions between the Hat1 core complex and an N1 family histone chaperone may also occur in the cytoplasm as an early step in the chromatin assembly pathway. These results derived from experiments involving the fractionation of epitope-tagged histones from cytoplasmic extracts [61]. One important caveat of these experiments is that nuclear proteins that are not stably associated with chromatin can readily leak out of the nucleus during the preparation of cytoplasmic extracts making it difficult to definitively determine sub-cellular localization. In addition, immuno-localization studies of the NuB4 complex components in both yeast and human cells show that these factors are highly enriched in the nucleus [65], [96], [97], [102], [103]. Therefore, it is likely that the bulk of the NuB4 complex is in the nucleus and that if this complex is found in the cytoplasm, it is likely to be a transient intermediate in the histone deposition process. An important question for future studies is whether the Hat1-containing complexes found in the cytoplasm and nucleus perform distinct activities or whether they are functionally related.