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KAT2A  -  K(lysine) acetyltransferase 2A

Homo sapiens

Synonyms: GCN5, GCN5L2, General control of amino acid synthesis protein 5-like 2, HGCN5, Histone acetyltransferase GCN5, ...
 
 
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Disease relevance of GCN5L2

 

High impact information on GCN5L2

  • Here, we show that Ash1 functions as a repressor that inhibits SWI/SNF binding and that Gcn5 is required to overcome Ash1 repression in mother cells to allow HO transcription [2].
  • These findings support the view that Gcn5 and PCAF have distinct roles in vivo and suggest a new mechanism of coactivator function, in which a single adaptor protein (Ada2beta) can coordinate targeting of both histone acetylation and chromatin remodeling activities [3].
  • However, in contrast to yeast Gcn5p and the previously reported shorter form of hsGCN5, mmGCN5 readily acetylates nucleosomal substrates as well as free core histones [4].
  • Mapping of the 17q21 breakpoint by fluorescence in situ hybridization within a specific region in three tumors revealed several positional candidates including GCN5L2, a gene with histone acetyltransferase activity similar to those fused to MORF in AML [5].
  • In this simplified model for gene activation VP16 recruits the general factors and the cofactors Mediator, GCN5, CBP, and PC4, within minutes to the promoter region [6].
 

Biological context of GCN5L2

 

Anatomical context of GCN5L2

  • Adenoviral-mediated expression of GCN5 in cultured hepatocytes and in mouse liver largely represses activation of gluconeogenic enzymes and decreases hepatic glucose production [11].
  • It was suggested that TSA as HDACIs could increase the expression of hGCN5 in Daudi cells, and might play an important role in regulating the proliferation and apoptosis of B-NHL cell line Daudi cells [1].
 

Chemical compound and disease context of GCN5L2

 

Associations of GCN5L2 with chemical compounds

  • The GCN5 bromodomain binds the small ligands N(omega)-acetylhistamine and N-methylacetamide, confirming specificity for the alkyl acetamide moiety and showing that the primary element of recognition is simply the sterically unhindered terminal acetamide moiety of an acetylated lysine residue [13].
  • Utilizing a novel microplate fluorescent HAT assay which detects the enzymatic production of coenzyme A (CoA), we have compared the activities of the HAT domains of human PCAF and its GCN5 homologue from yeast and Tetrahymena and found that they have similar kinetic parameters [14].
  • Both modifications lead to the binding of specific proteins; bromodomain proteins, such as GCN5, bind acetyl lysines and the chromodomain protein, HP1, binds methyl lysine 9 of histone H3 [15].
  • Trichostatin A regulates hGCN5 expression and cell cycle on daudi cells in vitro [1].
  • We show that C/EBPbeta is acetylated by GCN5 and PCAF within a cluster of lysine residues between amino acids 98-102 and that this acetylation is strongly induced by glucocorticoid treatment [16].
 

Physical interactions of GCN5L2

 

Regulatory relationships of GCN5L2

  • Taken together, these experiments support a multistep model of transcriptional initiation wherein the binding of T3 to hTRbeta1 initiates the recruitment of p160 coactivators and GCN5 to form a trimeric transcriptional complex that activates target genes through interactions with ADA/SAGA adaptor proteins and nucleosomal histones [18].
 

Other interactions of GCN5L2

  • While hsGCN5 was predicted to be close to the size of the yeast acetyltransferase, hsP/CAF contained an additional 356 amino-terminal residues of unknown function [4].
  • Northern blot analysis across a range of human tissues revealed that both the TADA2L and the GCN5L2 mRNAs are expressed to varying degrees in all tissue types [7].
  • Here we show that Myc co-recruits TRRAP and GCN5 via direct physical interactions of its N-terminal activation/transformation domain with the human STAGA (SPT3-TAF-GCN5 acetylase) coactivator complex [19].
  • In assays of isolated enzymes, CI-994 inhibited HDAC-1 and HDAC-2 in a concentration-dependent fashion but had no effect on the activity of the prototypical histone acetyltransferase GCN5 [20].
 

Analytical, diagnostic and therapeutic context of GCN5L2

References

  1. Trichostatin A regulates hGCN5 expression and cell cycle on daudi cells in vitro. Liu, H., Chen, Y., Cui, G., Wu, G., Wang, T., Hu, J. J. Huazhong Univ. Sci. Technol. Med. Sci. (2006) [Pubmed]
  2. SWI/SNF binding to the HO promoter requires histone acetylation and stimulates TATA-binding protein recruitment. Mitra, D., Parnell, E.J., Landon, J.W., Yu, Y., Stillman, D.J. Mol. Cell. Biol. (2006) [Pubmed]
  3. A novel human Ada2 homologue functions with Gcn5 or Brg1 to coactivate transcription. Barlev, N.A., Emelyanov, A.V., Castagnino, P., Zegerman, P., Bannister, A.J., Sepulveda, M.A., Robert, F., Tora, L., Kouzarides, T., Birshtein, B.K., Berger, S.L. Mol. Cell. Biol. (2003) [Pubmed]
  4. Mammalian GCN5 and P/CAF acetyltransferases have homologous amino-terminal domains important for recognition of nucleosomal substrates. Xu, W., Edmondson, D.G., Roth, S.Y. Mol. Cell. Biol. (1998) [Pubmed]
  5. Uterine leiomyomata with t(10;17) disrupt the histone acetyltransferase MORF. Moore, S.D., Herrick, S.R., Ince, T.A., Kleinman, M.S., Cin, P.D., Morton, C.C., Quade, B.J. Cancer Res. (2004) [Pubmed]
  6. The VP16 Activation Domain Establishes an Active Mediator Lacking CDK8 in Vivo. Uhlmann, T., Boeing, S., Lehmbacher, M., Meisterernst, M. J. Biol. Chem. (2007) [Pubmed]
  7. The human transcriptional adaptor genes TADA2L and GCN5L2 colocalize to chromosome 17q12-q21 and display a similar tissue expression pattern. Carter, K.C., Wang, L., Shell, B.K., Zamir, I., Berger, S.L., Moore, P.A. Genomics (1997) [Pubmed]
  8. Histone acetylase GCN5 enters the nucleus via importin-alpha in protozoan parasite Toxoplasma gondii. Bhatti, M.M., Sullivan, W.J. J. Biol. Chem. (2005) [Pubmed]
  9. Fluorescence analysis of a dynamic loop in the PCAF/GCN5 histone acetyltransferase. Zheng, Y., Mamdani, F., Toptygin, D., Brand, L., Stivers, J.T., Cole, P.A. Biochemistry (2005) [Pubmed]
  10. P/CAF and GCN5 acetylate the AML1/MDS1/EVI1 fusion oncoprotein. Senyuk, V., Sinha, K.K., Chakraborty, S., Buonamici, S., Nucifora, G. Biochem. Biophys. Res. Commun. (2003) [Pubmed]
  11. GCN5 acetyltransferase complex controls glucose metabolism through transcriptional repression of PGC-1alpha. Lerin, C., Rodgers, J.T., Kalume, D.E., Kim, S.H., Pandey, A., Puigserver, P. Cell metabolism. (2006) [Pubmed]
  12. GCN5-mediated transcriptional control of the metabolic coactivator PGC-1beta through lysine acetylation. Kelly, T.J., Lerin, C., Haas, W., Gygi, S.P., Puigserver, P. J. Biol. Chem. (2009) [Pubmed]
  13. Solution structure and acetyl-lysine binding activity of the GCN5 bromodomain. Hudson, B.P., Martinez-Yamout, M.A., Dyson, H.J., Wright, P.E. J. Mol. Biol. (2000) [Pubmed]
  14. Application of a fluorescent histone acetyltransferase assay to probe the substrate specificity of the human p300/CBP-associated factor. Trievel, R.C., Li, F.Y., Marmorstein, R. Anal. Biochem. (2000) [Pubmed]
  15. Histone H3 lysine 4 methylation disrupts binding of nucleosome remodeling and deacetylase (NuRD) repressor complex. Zegerman, P., Canas, B., Pappin, D., Kouzarides, T. J. Biol. Chem. (2002) [Pubmed]
  16. Glucocorticoid-stimulated preadipocyte differentiation is mediated through acetylation of C/EBPbeta by GCN5. Wiper-Bergeron, N., Salem, H.A., Tomlinson, J.J., Wu, D., Haché, R.J. Proc. Natl. Acad. Sci. U.S.A. (2007) [Pubmed]
  17. The transforming acidic coiled coil proteins interact with nuclear histone acetyltransferases. Gangisetty, O., Lauffart, B., Sondarva, G.V., Chelsea, D.M., Still, I.H. Oncogene (2004) [Pubmed]
  18. GCN5 and ADA adaptor proteins regulate triiodothyronine/GRIP1 and SRC-1 coactivator-dependent gene activation by the human thyroid hormone receptor. Anafi, M., Yang, Y.F., Barlev, N.A., Govindan, M.V., Berger, S.L., Butt, T.R., Walfish, P.G. Mol. Endocrinol. (2000) [Pubmed]
  19. c-Myc transformation domain recruits the human STAGA complex and requires TRRAP and GCN5 acetylase activity for transcription activation. Liu, X., Tesfai, J., Evrard, Y.A., Dent, S.Y., Martinez, E. J. Biol. Chem. (2003) [Pubmed]
  20. Modulation of histone acetylation by [4-(acetylamino)-N-(2-amino-phenyl) benzamide] in HCT-8 colon carcinoma. Kraker, A.J., Mizzen, C.A., Hartl, B.G., Miin, J., Allis, C.D., Merriman, R.L. Mol. Cancer Ther. (2003) [Pubmed]
 
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