Date of Award

8-1-2015

Degree Name

Doctor of Philosophy

Department

Molecular Biology, Microbiology and Biochemistry

First Advisor

Bhaumik, Sukesh

Abstract

Ribosomal protein genes are crucial for ribosome biogenesis. The ribosome itself is responsible for protein synthesis and hence cellular growth and development. Intertwining network of proteins in conjugation with cellular environment such as nutrition and growth factors collectively regulate expression of the ribosomal protein genes. DNA microarray analysis has implicated the role of 26S proteasome in transcriptional regulation of the ribosomal protein genes tying protein degradation to protein synthesis pathway. To determine the mechanism as to how the 26S proteasome promotes transcription of the ribosomal protein genes a series of experiments were performed. The results reveal that the 19S subcomplex of the 26S proteasome is recruited to the promoters of the ribosomal protein genes in a TOR (Target of Rapamycin)-dependent manner. TOR signals environmental cues and controls the expression of the ribosomal protein genes. Thus recruited 19S proteasome subcomplex promotes transcriptional initiation via facilitation of the recruitment of co-activator NuA4 (Nucleasome acetyltransferase of histone H4) complex to activator Rap1. NuA4 enhances PIC (Pre-initiation complex) formation at the core promoter, but it is not clearly understood how does it do so. Researches have identified two different forms of TBP: TAF (TBP associated factor)-dependent form of TBP and TAF-independent form of TBP. This work shows that impaired association of NuA4 interferes with TFIID recruitment, but recruits TAF-independent form of TBP to the core promoter. This recruitment of TBP is dependent on SAGA (Spt-Ada-Gcn5-acetyltransferase). Like ribosomal protein genes, antisense transcription is also enhanced by TAFs. However, it remains unknown whether NuA4 also promotes TAF-regulated antisense transcription. The results illustrate that like ribosomal protein genes, transcription of GAL10 antisense is also promoted by NuA4 HAT (histone acetyl transferase). NuA4 HAT is recruited to the 3’-end of the GAL10 coding sequence, acetylates histone H4 and promotes GAL10 antisense transcription. This work also reveals the roles of other chromatin regulatory factors in controlling antisense transcription. Collectively, these results significantly advance our current understanding of the regulatory mechanisms of ribosomal protein genes’ expression and antisense transcription. The ribosome and antisense are involved in virtually all the biological processes. Aberrant expression of the ribosomal protein genes and antisense transcripts are associated with numerous human disorders including cancers and cardiovascular diseases. Therefore, analyses of their regulatory processes provide valuable information toward understanding the etiology of numerous human diseases with potential therapeutic interventions.

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