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  • The importance of the histone chaperone function of


    The importance of the histone chaperone function of Hat1p was highlighted by the recent demonstration that the catalytic activity of Hat1p is not sufficient for its function in vivo. Fusion of a nuclear export signal (NES) to yeast Hat1p effectively excluded the enzyme from the nucleus, with a concomitant increase in cytoplasmic localization. Also, the NES–Hat1p fusion did not diminish the catalytic activity of the enzyme. Importantly, the presence of this catalytically active Hat1p in the cytoplasm was not sufficient to compensate for the defect in telomeric silencing seen in the absence of Hat1p [120]. Hence, the ability of Hat1p to localize to the nucleus, and not just its enzymatic activity, contributes to its cellular function.
    A model of HAT1 function The original view of Hat1 as an enzyme that simply generated the diacetylation of newly synthesized histone H4 as an early step in histone deposition is not consistent with recent results. Rather, the role of Hat1 should be viewed as an integral component of the Dextran sulfate sodium salt synthesis assembly process that may function at multiple steps. The basic features of a current model for Hat1 function are shown in Fig. 1. The process of chromatin assembly is considered to be a step-wise process involving the sequential action of a series of enzymes and histone chaperones [118], [121]. Our understanding of these steps has become clearer with the identification of several discreet complexes containing soluble histones H3 and H4. The first factors that interact with newly synthesized H3 and H4 appear to be the heat shock factors HSC70 and HSP90, with HSC70 found with H3 and HSP90 with H4 [43], [61]. These factors are likely to assist in the folding of the newly synthesized histone molecules into complexes with the appropriate stoichiometries [99], [122]. The evidence that these heat shock proteins function upstream of Hat1 comes from the observation that the histone H4 associated with these factors is not acetylated on lysine 12 [61]. As all other soluble H3/H4-containing complexes that have been identified contain H4 lysine 12 acetylation, it is likely that interaction with Hat1 is the next step in the histone deposition pathway [61], [105]. It is also likely that this initial interaction between the Hat1–Hat2(Rbap46) complex and histones H3/H4 occurs in the cytoplasm. However, while there is conflicting evidence as to whether Hif1p(NASP) is associated with the cytoplasmic HAT1 complex, overall, the evidence suggests that the bulk of this interaction occurs in the nucleus and that a significant fraction of the cytoplasmic Hat1–Hat2(Rbap46) complex is independent of Hif1(NASP) [50], [61], [96], [97], [98], [107]. The fate of the Hat1 complex following its initial interaction with histones H3/H4 and the acetylation of H4 lysines 5 and 12 is not entirely clear. One possibility is that Asf1 interacts with the Hat1 complex to facilitate the transfer of the histones to the proper karyopherin/importin for nuclear import. Data showing that Asf1 interacts with both the Hat1-containing complexes and with the karyopherins/importins and that the histone H4 bound to the import factors is acetylated on lysine 12 supports this sequence of events [61], [105]. However, it is not known whether all of the histones associated with the cytoplasmic Hat1 are funneled into this Asf1/karyopheric pathway. Given that Hat1-containing complexes are stably associated with histones H3 and H4 in both the cytoplasm and the nucleus, it is not unreasonable to speculate that the Hat1 complexes may play a more direct role in the nuclear import of the histones [96], [111]. The presence of multiple mechanisms for histone nuclear import is supported by the fact that loss of the primary histone binding karyopherin/importin does not cause a dramatic defect in histone nuclear import [111]. Regardless of whether it is co-transported with histones H3 and H4 or whether it transits to the nucleus independently, the function of Hat1 once it is in the nucleus is not well understood. While in the nuclear compartment, Hat1, in all likelihood, exists in several distinct pools. For example, biochemical evidence indicates that a Hat1–Hat2(Rbap46) complex exists that does not contain a Hif1p(NASP) subunit and is consistent with the interaction of this complex with ORC occurring independently of Hif1p [98], [108]. It is undetermined whether the binding of the Hat1–Hat2(Rbap46) complex with the ORC complex occurs in the context of simultaneous binding to histone H3 and H4. In addition, it is not clear whether this interaction is related to replication-coupled chromatin assembly or whether this interaction is directly involved in the DNA replication process.