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INTERROGATING THE ROLE OF N6-METHYLADENOSINE RNA MODIFICATION ON TELOMERASE BIOLOGY
Fox, Cameron
Fox, Cameron
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Abstract
Telomerase is a multisubunit ribonucleoprotein complex that is used by most eukaryotes to restore the terminal DNA of chromosomes lost during replication. The RNA subunit of telomerase, TERC, hTR acts as a template for its reverse transcriptase activity and as a scaffold for the binding of proteins involved in the maturation, stabilization, and trafficking of the telomerase holoenzyme. Mutations or inefficient processing of hTR leads to degenerative diseases such as idiopathic pulmonary fibrosis and aplastic anemia. Due to the severe nature of these diseases and absence of pharmaceutical interventions, it is important to understand the regulation of hTR in hopes that drug targets can be identified. The 3’ processing of the hTR has recently been studied in detail and shown to be a dynamic process that balances processing with degradation to produce mature hTR. My work has identified hTR to be an N6-methyladenosine (m6A) modified RNA. The presence of m6A adds another layer of complexity to hTR processing due to the ability of the mark to be added to specific RNA and act as a target for m6A selective RNA binding proteins. In the case of hTR, the addition of m6A is in competition with binding of dyskerin, a protein that stabilizes the RNA. If m6A is added to hTR, it acts as a target for the recruitment of degradation machinery, which removes the modified RNA. This shows that the addition of m6A is a quality control step during the maturation of hTR. The loss of m6A on hTR leads to an accumulation of mature and immature transcripts, suggesting that normal processing can occur without the modification and that m6A only affects the degradation pathway of hTR. These findings provide insight into how levels of hTR accumulation are controlled as well as describe a new adaptor for the nuclear exosome.
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2019-01-01
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University of Kansas
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Molecular biology