Acetylation, Activation, and Toxicity: The Role of ADA/GCN5 Complex in Transcription

  • N. Silverman
  • L. Guarente
Part of the Nucleic Acids and Molecular Biology book series (NUCLEIC, volume 11)


The activation of transcription is a fundamental means of gene regulation. In eukaryotes a key component involved in transcriptional activation is the transcriptional activator. The activator functions by virtue of two, often separable, domains. The DNA binding domain is necessary for the activator to bind to specific DNA sequences found near the gene(s) which it regulates. The other domain, the activation domain, mediates the stimulation of transcription of that nearby gene (Hope and Struhl 1986). The mechanism by which these activation domains influence the rate of transcription has been the focus of much research over the last decade.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Barlev NA, Candau R, Wang L, Darpino P, Silverman N, Berger SL (1995) Characterization of physical interactions of the putative transcriptional adaptor, ADA2, with acidic activation domains and TATA-binding protein. J Biol Chem 270: 19337–19334PubMedCrossRefGoogle Scholar
  2. Berger SL, Cress WD, Cress A, Triezenberg SJ, Guarente L (1990) Selective inhibition of activated but not basal transcription by the acidic activation domain of VP16: evidence for transcriptional adaptors. Cell 61:1199–1208PubMedCrossRefGoogle Scholar
  3. Berger SL, Piña B, Silverman N, Marcus GA, Agapite J, Regier JL, Triezenberg SJ, Guarente L (1992) Genetic isolation of ADA2: a potential transcriptional adaptor required for function of certain acidic activation domains. Cell 70:251—265PubMedCrossRefGoogle Scholar
  4. Brandl CJ, Furlanetto AM, Martens J A, Hamilton K (1993) Characterization of NGG1, a novel yeast gene required for glucose repression of GAL4p-regulated transcription. EMBO J 12:5255–5265PubMedGoogle Scholar
  5. Brandl CJ, Martens JA, Margaliot A, Stenning D, Furlanetto AM, Saleh A, Hamilton KS, Genereaux J (1996) Structure/functional properties of the yeast dual regulator protein NGG1 that are required for glucose repression. J Biol Chem 271:9298–9306PubMedCrossRefGoogle Scholar
  6. Brownell JE, Allis CD (1995) An activity gel assay detects a single, catalytically active histone acetyltransferase subunit in Tetrahymena macronuclei. Proc Natl Acad Sci USA 92:6364–6368PubMedCrossRefGoogle Scholar
  7. Brownell JE, Allis CD (1996) Special HATs for special occasions: linking histone acetylation to chromatin assembly and gene activation. Curr Opin Genet Dev 6:176–185PubMedCrossRefGoogle Scholar
  8. Brownell JE, Zhou J, Ranalli T, Kobayashi R, Edmondson DG, Roth SY, Allis CD (1996) Tetrahymena histone acetyltransferase A: a homolog to yeast Gcn5p linking histone acetylation to gene activation. Cell 84:843–851PubMedCrossRefGoogle Scholar
  9. Candau R, Berger SL (1996) Structural and functional analysis of yeast putative adaptors. J Biol Chem 217:5237–5245Google Scholar
  10. Candau R, Moore PA, Wang L, Barlev N, Ying CY, Rosen CA, Berger SL (1996) Identification of human proteins functionally conserved with the yeast putative adaptors ADA2 and GCN5. Mol Cell Biol 16:593–602PubMedGoogle Scholar
  11. Chen JL, Attardi LD, Verrijzer CP, Yokomori K, Tjian R (1994) Assembly of recombinant TFIID reveals differential coactivator requirements for distinct transcriptional activators. Cell 79:93–105PubMedCrossRefGoogle Scholar
  12. Chrivia JC, Kwok RPS, Lamb N, Hagiwara M, Montminy MR, Goodman RH (1993) Phosphorylated CREB binds specifically to the nuclear protein CBP. Nature 365:855–859PubMedCrossRefGoogle Scholar
  13. Eckner R, Ewen ME, Newsome D, Gerdes M, DeCaprio JA, Lawrence JB, Livingston DM (1993) Molecular cloning and functional analysis of the adenovirus E1A-associated 300-kD protein (p300) reveals a protein with properties of a transcriptional adaptor. Genes Dev 8:869–884CrossRefGoogle Scholar
  14. Falvo JV, Thanos D, Maniatis T (1995) Reversal of intrinsic DNA bends in the INFβgene enhancer by transcription factors and the architectural protein HMG I(Y). Cell 83:1101–1112PubMedCrossRefGoogle Scholar
  15. Georgakopoulos T, Thireos G (1992) Two distinct yeast transcriptional activators require the function of the GCN5 protein to promote normal levels of transcription. EMBO J 11:4145–4152PubMedGoogle Scholar
  16. Gill G, Ptashne M (1988) Negative effect of the transcriptional activator GAL4. Nature 334:721–724PubMedCrossRefGoogle Scholar
  17. Goodrich J A, Tjian R (1994) TBP-TAF complexes: selectivity factors for eukaryotic transcription. Curr Opin Cell Biol 6:403–409PubMedCrossRefGoogle Scholar
  18. Goodrich JA, Hoey T, Thut CJ, Admon A, Tjian R (1993) Drosophila TAFII40 interacts with both a VP16 activation domain and the basal transcription factor TFIIB. Cell 75:519–530PubMedCrossRefGoogle Scholar
  19. Haynes SR, Dollard C, Winston F, Beck S, Trowsdale J, Dawid IB (1992) The bromodomain: a conserved sequence found in human, Drosophila and yeast proteins. Nucleic Acids Res 20:2603PubMedCrossRefGoogle Scholar
  20. Hebbes TR, Thorne AW, Crane-Robinson C (1988) A direct link between core histone acetylation and transcriptionally active chromatin. EMBO J 7:1395–1402PubMedGoogle Scholar
  21. Hebbes TR, Clayton AL, Thorne AW, Crane-Robinson C (1994) Core histone hyperacetylation co-maps with generalized DNasel sensitivity in the chicken β-globin chromosomal domain. EMBO J 13:1823–1320PubMedGoogle Scholar
  22. Hengartner CJ, Thompson CM, Zhang J, Chao DM, Liao SM, Koleske AJ, Okamura S, Young RA (1995) Association of an activator with an RNA polymerase II holoenzyme. Genes Dev 9:897–910PubMedCrossRefGoogle Scholar
  23. Hope I, Struhl K (1986) Functional dissection of a eukaryotic transcriptional activator protein, GCN4, of yeast. Cell 46:885–894PubMedCrossRefGoogle Scholar
  24. Horiuchi J, Silverman N, Marcus G, Guarente L (1995) ADA3, a putative transcriptional adaptor, consists of two separable domains and interacts with ADA2 and GCN5 in a trimeric complex. Mol Cell Biol 15:1203–1209PubMedGoogle Scholar
  25. Ingles CJ, Shales M, Cress WD, Triezenberg SJ, Greenblatt J (1991) Reduced binding of TFIID to transcriptionally compromised mutants of VP16. Nature 351:588–590PubMedCrossRefGoogle Scholar
  26. Kelleher RJ III, Flanagan PM, Kornberg RD (1990) A novel mediator between activa­tor proteins and the RNA polymerase II transcription apparatus. Cell 61:1209–1215PubMedCrossRefGoogle Scholar
  27. Kim TK, Hashimote S, Kelleher RJ, Flanagan PM, Kornberg RD, Horikoshi M, Roeder RG (1994) Effects of activation-defective TBP mutations on transcrip­tional initiation in yeast. Nature 369:252–255PubMedCrossRefGoogle Scholar
  28. Lin YS, Green MR (1991) Mechanism of action of an acidic transcriptional activator in vitro. Cell 64:971–981PubMedCrossRefGoogle Scholar
  29. Lin YS, Maldonado E, Reinberg D, Green MR (1991) Binding of general transcription factor TFIIB to an acidic activating region. Nature 353:569–571PubMedCrossRefGoogle Scholar
  30. Marcus GA, Silverman N, Berger SL, Horiuchi J, Guarente L (1994) Functional similarity and physical associatin between GCN5 and ADA2: putative transcriptional adaptors. EMBO J 13:4807–4815PubMedGoogle Scholar
  31. Marcus GA, Horiuchi J, Silverman N, Guarente L (1996) ADA5/SPT20 links the ADA and SPT genes involved in yeast transcription. Mol Cell Biol 16:3197–3205PubMedGoogle Scholar
  32. Moqtaderi Z, Bai Y, Poon D, Weil PA, Struhl K (1996) TBP-associated factors are not generally required for transcriptional activation in yeast. Nature 383:188–192PubMedCrossRefGoogle Scholar
  33. Paranjape SM, Kamakaka RT, Kadonaga JT (1994) Role of chromatin structure in the regulation of transcription by RNA polymerase II. Annu Rev Biochem 63:265–297PubMedCrossRefGoogle Scholar
  34. Paranjape SM, Krumm A, Kadonaga JT (1995) HMG17 is a chromatin-specific transcriptional coactivator that increases the efficiency of transcriptional initiation. Genes Dev 9:1978–1991PubMedCrossRefGoogle Scholar
  35. Peterson CL, Tamkum JW (1995) The SWI-SNF complex: a chromatin remodeling machine? TIBS 20:146Google Scholar
  36. Piña B, Berger S, Marcus GA, Silverman N, Agapite J, Guarente L (1993) ADA3: a gene, identified by resistance to GAL4-VP16, with properties similar to and different from those of ADA2. Mol Cell Biol 13:5981–5989PubMedGoogle Scholar
  37. Pugh BF, Tjian R (1990) Mechanism of transcriptional activation by Sp1: evidence for coactivators. Cell 61:1187–1197PubMedCrossRefGoogle Scholar
  38. Roberts S, Winston F (1996) SPT20/ADA5 encodes a novel protein functionally related to the TATA-binding protein and important for transcription in Saccharo-myces cerevisiae. Mol Cell Biol 16:3206–3213PubMedGoogle Scholar
  39. Roberts SGE, Green MR (1994) Activator-induced conformational change in general transcription factor TFIIB. Nature 371:717–720PubMedCrossRefGoogle Scholar
  40. Roberts SGE, Ha I, Maldonado E, Reinberg D, Green MR (1993) Interaction between an acidic activator and transcription factor IIB is required for transcriptional activation. Nature 363:741–744PubMedCrossRefGoogle Scholar
  41. Roth SY, Allis CD (1996) The subunit-exchange model of histone acetylation. Trends Cell Biol 6:371–375PubMedCrossRefGoogle Scholar
  42. Sauer F, Hansen SK, Tjian R (1995a) DNA template and activator-coactivator requirements for transcriptional synergism by Drosophila bicoid. Science 270: 1825–1828PubMedCrossRefGoogle Scholar
  43. Sauer F, Hansen SK, Tjian R (1995b) Multiple TAFIIs directing synergistic activation of transcription. Science 270:1783–1788PubMedCrossRefGoogle Scholar
  44. Shykind BM, Kim J, Sharp PA (1995) Activation of the TFIID-TFIIA complex with HMG-2 as coactivator. Genes Dev 9:1354–1365PubMedCrossRefGoogle Scholar
  45. Silverman N (1996) Genetic and biochemical characterization of the ADAs: a transcriptional adaptor complex. PhD Thesis, Massachusetts Institute of Technology, CambridgeGoogle Scholar
  46. Silverman N, Agapite J, Guarente L (1994) Yeast ADA2 protein binds to the VP16 protein activation domain and activates transcription. Proc Natl Acad Sci USA 91:11665–11668PubMedCrossRefGoogle Scholar
  47. Stringer KF, Ingles CJ, Greenblatt J (1990) Direct and selective binding of an acidic transcriptional activation domain to the TATA-box factor TFIID. Nature 345:783–786PubMedCrossRefGoogle Scholar
  48. Thanos D, Maniatis T (1995) Virus induction of human IFNβ gene expression requires the assembly of an enhanceosome. Cell 83:1091–1100PubMedCrossRefGoogle Scholar
  49. Walker SS, Reese JC, Apone LM, Green MR (1996) Transcription activation in cells lacking TAFIIs. Nature 383:185–188PubMedCrossRefGoogle Scholar
  50. Wilson CJ, Chao DM, Imbalzano AN, Schnitzler GR, Kingston RE, Young RA (1996) RNA polymerase II holoenzyme contains SWI/SNF regulators involved in chromatin remodeling. Cell 84:235–244PubMedCrossRefGoogle Scholar
  51. Winston F (1992) Analysis of SPT genes: a genetic approach toward analysis of TFIID, histones, and other transcription factors of yeast. In: McKnight SL, Yamamoto KR (eds) Transcriptional regulation. Cold Spring Harbor Laboratory Press, Cold Spring Harber, pp 1271–1293Google Scholar
  52. Wolffe A, Pruss D (1996) Targeting chromatin disruption: transcription regulators that acetylate histones. Cell 84:817–819PubMedCrossRefGoogle Scholar
  53. Wolffe AP (1994) Transcription: in tune with histones. Cell 77:13–16PubMedCrossRefGoogle Scholar
  54. Yang X, Ogryzko V, Nishikawa J, Howard J, Nakatani Y (1996) A p300/CBP-associated factor that competes with the adenoviral oncoprotein E1A. Nature 382:319–324PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1997

Authors and Affiliations

  • N. Silverman
    • 1
  • L. Guarente
    • 2
  1. 1.Department of Molecular and Cellular BiologyHarvard UniversityCambridgeUSA
  2. 2.Department of BiologyMITCambridgeUSA

Personalised recommendations