Date of Award

Fall 10-2021

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

School

Biological, Environmental, and Earth Sciences

Committee Chair

Alex S. Flynt

Committee Chair School

Biological, Environmental, and Earth Sciences

Committee Member 2

Mohamed Elasri

Committee Member 2 School

Biological, Environmental, and Earth Sciences

Committee Member 3

YanLin Guo

Committee Member 3 School

Biological, Environmental, and Earth Sciences

Committee Member 4

Has Xu

Committee Member 4 School

Biological, Environmental, and Earth Sciences

Committee Member 5

Fengwei Bai

Committee Member 5 School

Biological, Environmental, and Earth Sciences

Abstract

Approximately a thousand microRNAs (miRNAs) are documented from human cells. A third appear to transit non-canonical pathways that typically bypass processing by Drosha, the dedicated nuclear miRNA producing enzyme. The largest class of non-canonical miRNAs are mirtrons which eschew Drosha to mature through spliceosome activity. While mirtrons are found in several configurations, the vast majority of human mirtron species are 5’-tailed. For these mirtrons, a 3’ splice site defines the 3’ end of their hairpin precursor while a “tail” of variable length separates the 5’ base of the hairpin from the nearest splice site. How this tail is removed is not understood. Here we examine sequence motifs in 5’-tailed mirtrons and interactions with RNA turnover processes to characterize biogenesis processes. Through studying the high confidence 5’-tailed mirtron, hsa-miR-5010, we identify RNaseP as necessary and sufficient for “severing” the 5’ tail of this mirtron. Further, depletion of RNaseP activity globally decreased 5’-tailed mirtron expression implicating this endoribonuclease in biogenesis of the entire class. Moreover, as 5’-tailed mirtron biogenesis appears to be connected to tRNA processing we found a strong correlation between accumulation of tRNA fragments (tRFs) and 5’-tailed mirtron abundance. This suggests that dysregulation of tRNA processing seem in cancers also impact expression of the ~400 5’-tailed mirtrons encoded in the human genome.

ORCID ID

https://orcid.org/0000-0002-2513-9565

Share

COinS