Date of Completion

4-26-2017

Embargo Period

4-26-2017

Keywords

RNA, Splicing, Genetics, ARGLU1, SR-like protein

Major Advisor

Dr. Gordon G. Carmichael

Associate Advisor

Stormy J Chamberlain

Associate Advisor

Brenton R Graveley

Associate Advisor

Arthur Günzl

Field of Study

Biomedical Science

Degree

Doctor of Philosophy

Open Access

Open Access

Abstract

ARGLU1 is a well conserved protein whose function is not well understood. I will show that ARGLU1 is an alternatively spliced gene, with at least three alternatively spliced isoforms. The main isoform codes for a nuclear protein that has been associated with the mediator transcriptional regulation complex as well as components of the spliceosome. One alternative isoform of ARGLU1 retains a single unspliced intron, even though all other introns have been removed, and is localized exclusively in the nucleus. A second alternative isoform causes inclusion of a premature termination codon, and is quickly degraded by the nonsense mediated decay quality control pathway. Interestingly, the retained intron contains an ultraconserved element, which is more than 95% conserved between human and chicken for over 500 bases. I will show that this ultraconserved element plays a key role in the alternative splicing of ARGLU1. Furthermore, I will show that exogenous overexpression of ARGLU1 leads to dramatic changes in alternative splicing of its own endogenous mRNA, causing a decrease in the protein coding isoform, and an increase in the retained intron and nonsense mediated decay targeted isoforms. Additionally, overexpression of ARGLU1 causes changes in mRNA levels and alternative splicing in a number of genes. Taken together, these results indicate that ARGLU1 can regulate its own splicing to regulate cellular protein levels. Furthermore, these results suggest that ARGLU1 plays a role in cellular alternative splicing.

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