Multidisciplinary investigations on tRNA modifications: a cmnm5(s2)U case study

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Fonderson, Cynthia D. E.
University of Lethbridge. Faculty of Arts and Science
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Lethbridge, Alta. : University of Lethbridge, Dept. of Chemistry and Biochemistry
Although tRNA modifications 5-carboxymethylaminomethyl(-2-thio)uridine (cmnm5(s2)U; and their human homologs) have been linked to mitochondrial disorders, their effects in vivo remain unknown. Furthermore, due to a lack of structural evidence, controversy exists in the literature pertaining to the assembly and catalytic mechanism of the MnmEG complex that introduces these modifications in tRNA. This thesis used a multidisciplinary approach to study the MnmEG modification complex and the effects of cmnm5(s2)U on tRNA structure. Biochemical studies reveal the binding propensities of MnmE and MnmG to their tRNA substrate, contributing vital experimental evidence towards the isolation of the MnmEG-tRNA complex. Concurrently, computational studies uncover the structural and cooperative properties of cmnm5(s2)U in biologically relevant tRNAs, providing the first atomic-level details of the function of these modifications in translation. Overall, this thesis lays the foundation for further explorations into this tRNA modification family and its relation to disease.
tRNA modification , MnmEG complex , cmnm5(s2)U