The adenoviral oncoprotein E1A induces progression through the cell cycle by binding to the products of the p300/CBP and retinoblastoma gene families. A new cellular p300/CBP-associated factor (P/CAF) having intrinsic histone acetylase activity has been identified that competes with E1A. Exogenous expression of P/CAF in HeLa cells inhibits cell-cycle progression and counteracts the mitogenic activity of E1A. E1A disturbs the normal cellular interaction between p300/CBP and its associated histone acetylase.

Protein lysine deacetylases play a pivotal role in numerous biological processes and are divided into the Rpd3/Hda1 and sirtuin families, each having members in diverse organisms including prokaryotes. In vertebrates, the Rpd3/Hda1 family contains eleven members, traditionally referred to as histone deacetylases (HDACs) 1-11 and grouped into distinct classes. While most class I HDACs are subunits of multiprotein nuclear complexes crucial for transcriptional repression and epigenetic landscaping, class II members regulate cytoplasmic processes or act like signal transducers trafficking between the cytoplasm and the nucleus. This review focuses on recent findings related to the Rpd3/Hda1 family with an emphasis on evolutionarily conserved domain organization, protein complex formation, regulation, and biological function.

PCAF histone acetylase plays a role in regulation of transcription, cell cycle progression, and differentiation. Here, we show that PCAF is found in a complex consisting of more than 20 distinct polypeptides. Strikingly, some polypeptides are identical to TBP-associated factors (TAFs), which are subunits of TFIID. Like TFIID, histone fold-containing factors are present within the PCAF complex. The histone H3- and H2B-like subunits within the PCAF complex are identical to those within TFIID, namely, hTAF(II)31 and hTAF(II)20/15, respectively. The PCAF complex has a novel histone H4-like subunit with similarity to hTAF(II)80 that interacts with the histone H3-like domain of hTAF(II)31. Moreover, the PCAF complex has a novel subunit with WD40 repeats having a similarity to hTAF(II)100.

The acetylation of histones increases the accessibility of nucleosomal DNA to transcription factors [1,2], relieving transcriptional repression [3] and correlating with the potential for transcriptional activity in vivo [4 - 7]. The characterization of several novel histone acetyltransferases - including the human GCN5 homolog PCAF (p300/CBP-associated factor) [8], the transcription coactivator p300/CBP [9], and TAFII250 [10] - has provided a potential explanation for the relationship between histone acetylation and transcriptional activation. In addition to histones, however, other components of the basal transcription machinery might be acetylated by these enzymes and directly affect transcription. Here, we examine the acetylation of the basal transcriptional machinery for RNA polymerase II by PCAF, p300 and TAFII250. We find that all three acetyltransferases can direct the acetylation of TFIIEbetaand TFIIF, and we identify a preferred site of acetylation in TFIIEbeta. Human TFIIE consists of two subunits, alpha(p56) and beta(p34), which form a heterotetramer (alpha2 beta2) in solution ([11], reviewed in [12]). TFIIE enters the preinitiation complex after RNA polymerase II and TFIIF, suggesting that TFIIE may interact directly with RNA polymerase II and/or TFIIF [13,14]. In addition, TFIIE can facilitate promoter melting either in the presence or absence of TFIIH and can stimulate TFIIH-dependent phosphorylation of the carboxy-terminal domain of RNA polymerase II [15-18]. TFIIF has an essential role in both transcription initiation and elongation ([19,20], for review see [21]). We discuss the implications of the acetylation of TFIIEbetaand TFIIF for transcriptional control by PCAF, p300 and TAFII250.

SUMMARY The HBO1 HAT protein is the major source of histone H4 acetylation in vivo and has been shown to play critical roles in gene regulation and DNA replication. A distinctive characteristic of HBO1 HAT complexes is the presence of three PHD finger domains in two different subunits: tumor suppressor proteins ING4/5 and JADE1/2/3. Biochemical and functional analyses indicate that these domains interact with histone H3 N-terminal tail region, but with a different specificity towards its methylation status. Their combinatorial action is essential in regulating chromatin binding and substrate specificity of HBO1 complexes, as well as cell growth. Importantly, localization analyses on the human genome indicate that HBO1 complexes are enriched throughout the coding regions of genes, supporting a role in transcription elongation. These results underline the importance and versatility of PHD finger domains in regulating chromatin association and histone modification cross-talk within a single protein complex.

We have isolated a human RNA polymerase II complex that contains chromatin structure remodeling activity and histone acetyltransferase activity. This complex contains the Srb proteins, the Swi-Snf complex, and the histone acetyltransferases CBP and PCAF in addition to RNA polymerase II. Notably, the general transcription factors are absent from this complex. The complex was purified by two different methods: conventional chromatography and affinity chromatography using antibodies directed against CDK8, the human homolog of the yeast Srb10 protein. Protein interaction studies demonstrate a direct interaction between RNA polymerase II and the histone acetyltransferases p300 and PCAF. Importantly, p300 interacts specifically with the nonphosphorylated, initiation-competent form of RNA polymerase II. In contrast, PCAF interacts with the elongation-competent, phosphorylated form of RNA polymerase II.

HOX proteins are sequence-specific DNA-binding transcription factors that play a crucial role in the specification of anteroposterior identity in the animal embryo (20, 54). Conservation within the DNA-binding homeodomains results in different HOX proteins recognizing similar regulatory elements with only modest preferences (reviewed in reference 27). High-affinity DNA binding is achieved when HOX proteins are heterodimerized with partners of the PBC family (mammalian PBX, Drosophila Extradenticle [EXD], and Caenorhabditis elegans CEH-20) (55). Mammalian MEIS1 has been shown to independently dimerize with HOX proteins and with PBX (11,57,78). Recently, trimeric complexes encompassing all three homeoproteins, HOX-PBX-MEIS, have also been characterized (77, 79). The MEIS-related protein PREP1, also known as PKNOX1, can additionally form a dimer with PBX, as well as a trimeric complex with HOX and PBX partners (6,7,15,34). While the majority of HOX monomers recognize a DNA core motif of TAAT (23), HOX-PBX, HOX-MEIS, and PBX-MEIS heterodimers recognize larger motifs resulting in a higher affinity and specificity of DNA binding by these homeoproteins (49).A conserved motif with the consensus YPWM is found N terminal to the homeodomain of HOX proteins from paralogous groups 1 to 8. The YPWM motif contacts the PBX homeodomain and is strictly required for cooperative DNA binding by PBX and HOX partners (49,50). A conserved W in HOX proteins from groups 9 and 10 performs a similar function (12).The downstream targets of mammalian HOX proteins have been poorly characterized. The best-characterized targets are some Hox genes known to be positively autoregulated by their own products or cross-regulated by the products of other Hox genes (26,68,69). In these instances, HOX-PBX complexes act as activators of transcription. For example, the Hoxb1 autoregulatory element (ARE) contains three binding sites for HOX-PBX complexes. These sites are required to direct expression of a Hoxb1 transgene in rhombomere 4 (r4) of the developing hindbrain (68).Genetic and molecular studies have provided evidence supporting a negative regulatory role for HOX proteins (43). In the case of decapentaplegic (dpp) regulation in Drosophila, repression by HOX proteins dominates over activation (9). This implies active transcriptional repression by HOX proteins (9,25,46). In addition, in vitro mapping studies have characterized repression domains in different HOX proteins, as well as in the PBX partner (13,45,75). Therefore, HOX proteins may be activators or repressors in a context-dependent manner.By analogy to nuclear receptors, HOX-PBX complexes are likely to achieve transcriptional repression or activation through differential association with coactivators and corepressors (81). One class of coregulators are the histone acetyltransferases (HATs) and the histone deacetylases (HDACs), which modify chromatin as well as nonhistone proteins. The HATs include GCN5, PCAF, CREB-binding protein (CBP)/p300, the steroid receptor coactivator class, and the MY...

We describe here the identification and functional characterization of a novel human histone acetyltransferase, termed MORF (monocytic leukemia zinc finger protein-related factor). MORF is a 1781-residue protein displaying significant sequence similarity to MOZ (monocytic leukemia zinc finger protein). MORF is ubiquitously expressed in adult human tissues, and its gene is located at human chromosome band 10q22. MORF has intrinsic histone acetyltransferase activity. In addition to its histone acetyltransferase domain, MORF possesses a strong transcriptional repression domain at its N terminus and a highly potent activation domain at its C terminus. Therefore, MORF is a novel histone acetyltransferase that contains multiple functional domains and may be involved in both positive and negative regulation of transcription.