Doctoral Studies

Biomolecular Chemistry - Field

Topic name: How did the DNA genome evolve from RNA?


Oficiální zadání:
RNA modification is a new field that is now being referred to as Epitranscriptomics (Keegan et al., 2004; O’Connell et al., 2015). One of my reviews is the basis of this PhD project (McLaughlin and Keegan, 2014). The proposal is to look at protein structure and evolution of ribonucleotide reductases and thymidylate synthetase, the enzymes that now make DNA precursors, to see whether they once introduced enzymatic modifications into dsRNA genomes directly. Currently these are only known to work on RNA mononucleotides. My hypothesis is that they evolved to work on bases within dsRNA genomes first and changed to act on free mononucleotides as genomes came to be based on DNA. This may have been the origin of DNA genomes. Thymidylate synthetase is already known to bind its own RNA and the project will aim to determine if thymidylate synthetase methylates a specific uracil in its own mRNA. The experiment involving ribonucleotide reductase will be to determine if it can work on the most 3’ bases in a short single-stranded RNA or on an internal RNA base. It is possible that some ribonucleotide reductase enzymes, perhaps from some ancient type of cell, may have conserved a greater ability to interact with RNA than the enzymes present in humans and other model organisms. As one of the three classes of ribonucleotide reductases appears to have the potential to bind RNA, this needs to be evaluated by looking for conservation of positive charges on a long channel on the surface of the protein at the active site using sequence alignments, PyMOL and other modelling programs. Then the selected enzymes can be expressed for in vitro tests of RNA interaction and modification. References Keegan, L.P., Leroy, A., Sproul, D., and O'Connell, M.A. (2004). Adenosine deaminases acting on RNA (ADARs): RNA-editing enzymes. Genome Biol 5, 209. McLaughlin, P.J., and Keegan, L.P. (2014). Conflict RNA modification, host parasite co-evolution, and the origins of DNA and DNA-binding proteins1. Biochem Soc Trans 42, 1159-1167. O’Connell, M.A., Mannion, N.M., and Keegan, L.P. (2015). The Epitranscriptome and Innate Immunity. PLoS Genet 11, e1005687.
Liam Keegan, Ph.D., MS - supervisor

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