(from the application): In the eukaryotic cell nucleus, DNA is packaged by histones into nucleosomes, the repeating subunits of chromatin. The regulation of gene expression from chromatin requires the concerted action of gene specific activator and repressor proteins, general transcription factors and chromatin modifying activities. These enzymes include histone acetlytransferases (HATs) which acetylate the highly conserved lysine residues within histone tails. HAT activities are often found to be associated with large multiprotein coactivator complexes that contain components with identity or homology to known regulators of transcription. These observations have provided a direct molecular basis for the coupling of histone acetylation and the regulation of transcription. The modification of chromatin by acetylation is postulated to play a central role in the etiology of viral infection and cancer and in mechanism of nuclear hormone receptor action. HAT/coactivator proteins are known to associate with cellular oncoproteins and tumor suppressor proteins and have been described in certain translocations associated with leukemias. The goals of this proposal are to understand the biochemical mechanisms and unique functions of native histone acetyltransferase/coactivator complexes. This proposal focuses on a novel yeast acetyltransferase complex named SLIK (SAGA-Like), related in composition to the conserved SAGA HAT/coactivator activity. The identification of this complex has complicated certain genetic interpretations of Ada, Spt and TAFII protein function previously attributed to SAGA. The primary goals of this proposal include 1. Purification and identification of SLIK components, 2. Characterization of the function of individual complex subunits, and 3. Analysis of promoter and gene specificity of SAGA and SLIK complexes. These studies aim to reveal the potential roles of distinct SAGA forms in different activation pathways.
| Daniel, Jeremy A; Grant, Patrick A (2007) Multi-tasking on chromatin with the SAGA coactivator complexes. Mutat Res 618:135-48 |
| McMahon, Stacey J; Pray-Grant, Marilyn G; Schieltz, David et al. (2005) Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc Natl Acad Sci U S A 102:8478-82 |
| Daniel, Jeremy A; Pray-Grant, Marilyn G; Grant, Patrick A (2005) Effector proteins for methylated histones: an expanding family. Cell Cycle 4:919-26 |
| Torok, Michael S; Grant, Patrick A (2004) Histone acetyltransferase proteins contribute to transcriptional processes at multiple levels. Adv Protein Chem 67:181-99 |
| McMahon, Stacey J; Doyon, Yannick; Cote, Jacques et al. (2004) Identification and analysis of native HAT complexes. Methods Enzymol 377:154-67 |
| Ramakrishnan, Girija; Gilchrist, Carol A; Musa, Hussein et al. (2004) Histone acetyltransferases and deacetylase in Entamoeba histolytica. Mol Biochem Parasitol 138:205-16 |
| Daniel, Jeremy A; Torok, Michael S; Sun, Zu-Wen et al. (2004) Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription. J Biol Chem 279:1867-71 |
| Flinn, Elizabeth M; Wallberg, Annika E; Hermann, Stefan et al. (2002) Recruitment of Gcn5-containing complexes during c-Myc-dependent gene activation. Structure and function aspects. J Biol Chem 277:23399-406 |
| Balasubramanian, Ramakrishnan; Pray-Grant, Marilyn G; Selleck, William et al. (2002) Role of the Ada2 and Ada3 transcriptional coactivators in histone acetylation. J Biol Chem 277:7989-95 |
| Pray-Grant, Marilyn G; Schieltz, David; McMahon, Stacey J et al. (2002) The novel SLIK histone acetyltransferase complex functions in the yeast retrograde response pathway. Mol Cell Biol 22:8774-86 |
