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Abstract Header
REGULATORY ROLES OF G-QUADRUPLEX IN microRNA PROCESSING AND mRNA TRANSLATION
Author Info
Mirihana Arachchilage, Gayan S
ORCID® Identifier
http://orcid.org/0000-0001-9742-5977
Permalink:
http://rave.ohiolink.edu/etdc/view?acc_num=kent1469576783
Abstract Details
Year and Degree
2016, PHD, Kent State University, College of Arts and Sciences / Department of Chemistry.
Abstract
G-quadruplexes (GQs) are secondary structures that can be adopted by both DNA and RNA in the presence of monovalent cations and they are known to play important regulatory roles in a wide range of biological processes, such as, transcription, translation, splicing, mRNA localization, and telomere homeostasis. Although the functional roles of GQ structures have been extensively studied, the evolution of GQ structure is poorly understood. Thus, we investigated the evolutionary selection of GQ structures within the codon region (CDS) of mRNAs in a wide range of species and observed that the stable GQs are selected against within CDSs by synonymous codon usage. Furthermore, our results revealed context-dependent codon bias against the formation of stable GQs at the codon level resolution, thus delineating the evolutionary mechanism of GQ selection. Although a myriad of studies has reported the regulatory roles of GQs that are present in mRNAs, very little is known about the prevalence and functions of GQs in non-coding RNAs. We revealed the presence of GQ structures in precursor microRNA (pre-miRNA) and showed a regulatory role for GQs in miRNA biogenesis. Using a clinically important miRNA (miR-92b), we showed the existence of an equilibrium between GQ and the canonical stem-loop conformation which can regulate various stages of miRNA biogenesis such as nuclear export and Dicer-mediated maturation. Furthermore, we demonstrated that GQ structures can potentially be targeted in pre-miRNAs to treat diseases in which corresponding miRNAs are overexpressed. We showed that a rationally designed locked nucleic acid (LNA) oligonucleotide, which specifically binds with the GQ confirmation containing pre-miRNA can be used to treat non-small cell lung cancer where miR-92b is overexpressed. Although many different GQ binding ligands have been developed as therapeutics, the selectivity of these ligands is crucial to estimate the off-target effects. We developed an
in vitro
library screening approach to evaluate the selectivity of such ligands before proceeding into more detailed path of therapeutic development. Collectively, results from this set of studies not only elaborate our understanding of the structure-function relationship of RNAs and its clinical importance but also provide insight into the evolutionary selection of RNA secondary structures as regulatory elements.
Committee
Soumitra Basu (Advisor)
Roger Gregory (Committee Member)
Jacob Shelley (Committee Member)
Kristian Baker (Committee Member)
Ernest Freeman (Committee Member)
Pages
198 p.
Subject Headings
Biochemistry
;
Cellular Biology
;
Chemistry
;
Molecular Biology
Keywords
G-quadruplex
;
Dicer
;
pre-miRNA
;
microRNA
;
Codon bias
;
translation
;
microRNA biogenesis
;
library screening
;
LNA
;
lung cancer
;
RNA
;
RNA secondary structure
;
RNA switch
;
locked nucleic acids
;
miRNA therapeutics
;
in vitro selection
;
GQ switch
Recommended Citations
Refworks
EndNote
RIS
Mendeley
Citations
Mirihana Arachchilage, G. S. (2016).
REGULATORY ROLES OF G-QUADRUPLEX IN microRNA PROCESSING AND mRNA TRANSLATION
[Doctoral dissertation, Kent State University]. OhioLINK Electronic Theses and Dissertations Center. http://rave.ohiolink.edu/etdc/view?acc_num=kent1469576783
APA Style (7th edition)
Mirihana Arachchilage, Gayan.
REGULATORY ROLES OF G-QUADRUPLEX IN microRNA PROCESSING AND mRNA TRANSLATION.
2016. Kent State University, Doctoral dissertation.
OhioLINK Electronic Theses and Dissertations Center
, http://rave.ohiolink.edu/etdc/view?acc_num=kent1469576783.
MLA Style (8th edition)
Mirihana Arachchilage, Gayan. "REGULATORY ROLES OF G-QUADRUPLEX IN microRNA PROCESSING AND mRNA TRANSLATION." Doctoral dissertation, Kent State University, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1469576783
Chicago Manual of Style (17th edition)
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Document number:
kent1469576783
Download Count:
662
Copyright Info
© 2016, all rights reserved.
This open access ETD is published by Kent State University and OhioLINK.