Alternative titles; symbols
HGNC Approved Gene Symbol: KAT2B
Cytogenetic location: 3p24.3 Genomic coordinates (GRCh38) : 3:20,040,446-20,154,404 (from NCBI)
CBP (600140) and p300 (602700) are large nuclear proteins that bind to many sequence-specific factors involved in cell growth and/or differentiation, including c-jun (see 165160) and the adenoviral oncoprotein E1A. Based on its homology to yeast GCN5, which interacts with yeast GCN4 (a counterpart of c-Jun), Yang et al. (1996) identified a protein, designated P/CAF, that associates with p300/CBP. P/CAF encodes a predicted 832-amino acid protein that Yang et al. (1996) showed by RNA blotting to be expressed in all tissues, most strongly in heart and skeletal muscle. Yang et al. (1996) showed P/CAF to have in vitro and in vivo binding activity with CBP and p300. P/CAF competes with E1A for binding sites in p300/CBP. Yang et al. (1996) found that P/CAF has histone acetyl transferase activity with core histones and nucleosome core particles, which indicates that P/CAF plays a direct role in transcriptional regulation.
Zhong et al. (1998) reported that the transcriptional activity of NF-kappa-B is stimulated upon phosphorylation of its p65 subunit (164014) on serine-276 by protein kinase A (PKA). The transcriptional coactivator CBP/p300 associates with NF-kappa-B p65 through 2 sites, an N-terminal domain that interacts with the C-terminal region of unphosphorylated p65, and a second domain that only interacts with p65 phosphorylated on serine-276. Phosphorylation by PKA both weakens the interaction between the N- and C-terminal regions of p65 and creates an additional site for interaction with CBP/p300. Therefore, PKA regulates the transcriptional activity of NF-kappa-B by modulating its interaction with CBP/p300.
Sartorelli et al. (1999) showed that MYOD (159970) is directly acetylated by PCAF at evolutionarily conserved lysines (positions 99, 102, and 104). Acetylated MYOD displayed an increased affinity for its DNA target. Conservative substitutions of acetylated lysines with nonacetylatable arginines impaired the ability of MYOD to stimulate transcription and to induce conversion, indicating that acetylation of MYOD is functionally critical.
To elucidate the molecular basis of assembling the multiprotein activation complex, Demarest et al. (2002) undertook a structural and thermodynamic analysis of the interaction domains of CBP and the activator for thyroid hormone and retinoid receptors (TRAM1; 601937). Demarest et al. (2002) demonstrated that although the isolated domains are intrinsically disordered, they combine with high affinity to form a cooperatively folded helical heterodimer. The authors concluded that their study uncovers a unique mechanism, which they termed 'synergistic folding,' through which p160 coactivators recruit CBP to allow transmission of the hormone signal to the transcriptional machinery.
Okumura et al. (2006) showed that PCAF interacted physically and functionally with PTEN (601728). PCAF acetylated PTEN on lys125 and lys128 within the catalytic cleft essential for phosphoinositol phosphate specificity, and this acetylation depended on the presence of growth factors. Reduction of endogenous PCAF in human embryonic kidney cells using short hairpin RNA resulted in loss of PTEN acetylation in response to growth factors, and restored PTEN- mediated downregulation of PI3K signaling and induction of G1 cell cycle arrest. Acetylation-resistant PTEN mutants retained the ability to regulate PI3K and induce cell cycle arrest following PCAF overexpression.
Triboulet et al. (2007) showed that suppression of the polycistronic miRNA cluster miR17-92 (see 609416) by HIV-1, required for efficient viral replication, was dependent on the histone acetyltransferase Tat cofactor PCAF. The authors concluded that their results highlighted the involvement of the miRNA silencing pathway in HIV-1 replication and latency.
Xenaki et al. (2008) found that PCAF functioned as a cofactor for HIF1A (603348) in human osteosarcoma cell lines treated with desferrioxamine (DSFX), a hypoxia-mimicking compound. PCAF and HIF1A interacted in DSFX-treated cells, resulting in PCAF-dependent acetylation of HIF1A. PCAF was recruited to the hypoxia response element of a subset of HIF1A targets, including the proapoptotic gene BID (601997) and the angiogenic gene VEGF (192240). DSFX-treated cells also showed HIF1A-dependent apoptosis. DSFX treatment also reduced PCAF-dependent acetylation of the tumor suppressor p53 (TP53; 191170), which directed p53 toward induction of the cell cycle regulator p21 (CDKN1A; 116899) and away from proapoptotic p53 targets. Xenaki et al. (2008) concluded that PCAF functions as a coordinating factor in the regulation of HIF1A-mediated apoptosis and p53-dependent cell cycle progression.
Using mass spectrometry to identify subunits of the SPT3 (SUPT3H; 602947)-TAF9 (600822)-GCN5 (KAT2A; 602301)/PCAF acetylase (STAGA) and ADA2A (TADA2A; 602276)-containing (ATAC) histone acetyltransferase complexes in HeLa cells, Wang et al. (2008) showed that both complexes could incorporate either GCN5 or PCAF as acetyltransferase. Both complexes shared the common subunits ADA3 (TADA3; 602945) and STAF36 (CCDC101; 613374), but differed by the inclusion of several subunits, including ADA2B (TADA2B; 608790) in STAGA and ADA2A and the scaffolding protein YEATS2 (613373) in ATAC. Human ATAC and STAGA specifically acetylated nucleosomal histone H3 (see 602812), and ATAC repressed transcription of a reporter gene in a dose-dependent manner. Wang et al. (2008) concluded that STAGA and ATAC complexes link extracellular signals to modification of chromatin structure and regulation of the basal transcriptional machinery.
Hartz (2009) mapped the KAT2B gene to chromosome 3p24.3 based on an alignment of the KAT2B sequence (GenBank U57317) with the genomic sequence (GRCh37).
By linkage analysis with an interspecific backcross panel, Xu et al. (1998) mapped the mouse Pcaf gene to the centromeric region of chromosome 17.
Goncalves et al. (2018) identified a homozygous F307S (c.920T-C, NM_003884.4) mutation in the KAT2B gene and a homozygous E659Q (c.1975G-C, NM_016824.4) mutation in the ADD3 gene (601568) in 3 sibs, born to consanguineous parents, from a family (family A) with spastic quadriplegic cerebral palsy-3 (CPSQ3; 617008). ADD3 protein levels were normal in patient fibroblasts, but KAT2B protein was reduced compared to controls. In addition to previously reported features of impaired intellectual development and microcephaly in CPSQ3, the 3 sibs also had cardiomyopathy and steroid-resistant nephrotic syndrome, which Goncalves et al. (2018) attributed to the combined effects of the mutations in the ADD3 and KAT2B genes.
Goncalves et al. (2018) studied Drosophila that were hemizygous for a null mutation in the Gcn5 gene, a homolog for the KAT2B gene and its paralog KAT2A (602301). The flies died at a larval/early pupal stage. Gcn5 with a F304S mutation, which was homologous to a KAT2A F307S mutation, was expressed in the Gcn5-null flies and the resulting flies had decreased viability with early death. Expression of Gcn5 with an S478F mutation rescued the phenotype of the Gcn5-null flies.
Demarest, S. J., Martinez-Yamout, M., Chung, J., Chen, H., Xu, W., Dyson, H. J., Evans, R. M., Wright, P. E. Mutual synergistic folding in recruitment of CBP/p300 by p160 nuclear receptor coactivators. Nature 415: 549-553, 2002. [PubMed: 11823864] [Full Text: https://doi.org/10.1038/415549a]
Goncalves, S., Patat, J., Guida, M. C., Lachaussee, N., Arrondel, C., Helmstadter, M., Boyer, O., Gribouval, O., Gubler, M. C., Mollet, G., Rio, M., Charbit, M., and 13 others. A homozygous KAT2B variant modulates the clinical phenotype of ADD3 deficiency in humans and flies. PLoS Genet. 14: e1007386, 2018. Note: Erratum: PLoS Genet. 14: e1007748, 2018. [PubMed: 29768408] [Full Text: https://doi.org/10.1371/journal.pgen.1007386]
Hartz, P. A. Personal Communication. Baltimore, Md. 12/8/2009.
Okumura, K., Mendoza, M., Bachoo, R. M., DePinho, R. A., Cavenee, W. K., Furnari, F. B. PCAF modulates PTEN activity. J. Biol. Chem. 281: 26562-26568, 2006. [PubMed: 16829519] [Full Text: https://doi.org/10.1074/jbc.M605391200]
Sartorelli, V., Puri, P. L., Hamamori, Y., Ogryzko, V., Chung, G., Nakatani, Y., Wang, J. Y. J., Kedes, L. Acetylation of MyoD directed by PCAF is necessary for the execution of the muscle program. Molec. Cell 4: 725-734, 1999. [PubMed: 10619020] [Full Text: https://doi.org/10.1016/s1097-2765(00)80383-4]
Triboulet, R., Mari, B., Lin, Y.-L., Chable-Bessia, C., Bennasser, Y., Lebrigand, K., Cardinaud, B., Maurin, T., Barbry, P., Baillat, V., Reynes, J., Corbeau, P., Jeang, K.-T., Benkirane, M. Suppression of microRNA-silencing pathway by HIV-1 during virus replication. Science 315: 1579-1582, 2007. [PubMed: 17322031] [Full Text: https://doi.org/10.1126/science.1136319]
Wang, Y.-L., Faiola, F., Xu, M., Pan, S., Martinez, E. Human ATAC is a GCN5/PCAF-containing acetylase complex with a novel NC2-like histone fold module that interacts with the TATA-binding protein. J. Biol. Chem. 283: 33808-33815, 2008. [PubMed: 18838386] [Full Text: https://doi.org/10.1074/jbc.M806936200]
Xenaki, G., Ontikatze, T., Rajendran, R., Stratford, I. J., Dive, C., Krstic-Demonacos, M., Demonacos, C. PCAF is an HIF-1-alpha cofactor that regulates p53 transcriptional activity in hypoxia. Oncogene 27: 5785-5796, 2008. [PubMed: 18574470] [Full Text: https://doi.org/10.1038/onc.2008.192]
Xu, W., Edmondson, D. G., Roth, S. Y. Mammalian GCN5 and P/CAF acetyltransferases have homologous amino-terminal domains important for recognition of nucleosomal substrates. Molec. Cell. Biol. 18: 5659-5669, 1998. [PubMed: 9742083] [Full Text: https://doi.org/10.1128/MCB.18.10.5659]
Yang, X.-J., Ogryzko, V. V., Nishikawa, J., Howard, B. H., Nakatani, Y. A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382: 319-324, 1996. [PubMed: 8684459] [Full Text: https://doi.org/10.1038/382319a0]
Zhong, H., Voll, R. E., Ghosh, S. Phosphorylation of NF-kappa B by PKA stimulates transcriptional activity by promoting a novel bivalent interaction with the coactivator CBP/p300. Molec. Cell 1: 661-671, 1998. [PubMed: 9660950] [Full Text: https://doi.org/10.1016/s1097-2765(00)80066-0]