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Title: Mechanisms of RNA polymerase III transcriptional activation by c-Myc
Author: Kenneth, Niall S.
ISNI:       0000 0001 3597 3134
Awarding Body: University of Glasgow
Current Institution: University of Glasgow
Date of Award: 2006
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The Myc family of proto-oncogenes encodes transcription factors that play a pivotal role in regulating cellular proliferation, cellular growth, differentiation and apoptosis. To regulate cellular growth, it can activate a number of RNA polymerase II- transcribed genes which encode ribosomal proteins, translation factors and other components of the biosynthetic apparatus. c-Myc can also directly activate transcription by RNA polymerases I and III, thereby stimulating the production of ribosomal (r)RNA and transfer (t)RNA. As such, c-Myc may possess the capacity to induce the expression of all the ribosomal components. The work in this project aimed to investigate the mechanisms behind the c-Myc-dependent activation of RNA polymerase III transcription. One mechanism by which activators of pol III transcription can stimulate the expression of class III genes is by promoting transcription complex formation. It had been previously demonstrated that c-Myc can interact with the pol Ill-specific transcription factor TFIIIB. Work in this thesis has further defined this interaction and demonstrated that activation of transcription by c-Myc can recruit this complex along with pol III to 5S rRNA and tRNA genes in vivo. Furthermore, the recruitment of TFIIIB and polymerase by c-Myc are distinct events, with a significant delay between TFIIIB and pol III binding, arguing against a pol III holoenzyme being recruited to the genes. Most recent work on the mechanisms of transcriptional activation by c-Myc has focussed on its ability to influence chromatin structure. Transcriptional activation of target genes by c-Myc may involve the remodelling of nucleosomes, since c-Myc has been shown to bind to the Snf5 subunit of the SWI/SNF complex, as well as the ATPase/helicases TIP48 and TIP49. In the present study, Snf5 and Brg1, both components of SWI/SNF, have been found at the promoters of pol Ill-transcribed genes. These may have a role in the regulation of pol III transcriptional activity. c-Myc can also recruit a variety of histone modifying enzymes to the promoters of its target genes. It can bind to the co-factor TRRAP, a 440 kDa protein that forms the scaffold of a variety of histone acetyltransferase complexes. It has been demonstrated that c-Myc can recruit these complexes to certain target genes, and the increase in histone acetylation correlates with gene expression. The TRRAP co-factor along with an associated HAT was found to be present in a c-Myc-sensitive manner on pol Ill- transcribed genes, and their presence correlated with histone acetylation and gene expression. In addition to these findings, depletion of endogenous TRRAP by RNAi in cultured cells resulted in a specific down-regulation of pol III transcription in vivo. In summary, this thesis has identified previously undescribed mechanisms by which c-Myc can activate transcription by pol III, and has identified novel co-activator proteins involved in the regulation of class III gene expression. This work has important implications in understanding the molecular basis of how activators can stimulate the expression of pol Ill-transcribed genes.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral