Biomedical Sciences Institute
Trinity College Dublin
Pearse Street
Dublin 2.
Phone: +353-1-896 3507
Fax: +353-1-677 2086
Email: kellyvp@tcd.ie

RNA is made from only four bases, adenine, guanine, cytosine and uracil. Yet, by folding into various three dimensional structures, RNA has the ability to facilitate numerous essential tasks of the cell. Consider, for example, the complexity of protein translation, where messenger RNA (mRNA), transfer RNA (tRNA) and the ribosome (comprising four RNA species and 79 proteins in mammals) co-operate to decode the genomic information into protein, as represented by the cartoon. To redress the paucity of primary sequence information, RNA is highly decorated by post-transcriptional chemical modifications, particularly in the case of tRNA. These modifications, which now number more than 95, impart new properties on the molecule such as increased stability or influence the codon recognition process.

The research of my laboratory focuses on modifications that occur on transfer RNA (tRNA) and their role in eukaryotic development and cancer. In particular, our recent efforts have focused on a modification called queuosine, which occurs in the anticodon loop of GUN tRNA, i.e. those that accept tyrosine, histidine, asparagine and aspartic acid. Surprisingly, both the tRNA in the cytosol and in mitochondria (which produce their own tRNA) are modified. Bacteria synthesise queuosine on tRNA through multiple enzymatic steps. Eukaryotes, on the other hand, are unable to make queuosine and instead salvage the base of queuosine, called queuine, from bacteria in the gut flora and from food. In the diagram opposite, queuine enters the cell through an unknown transporter and is then inserted into tRNA by a complex composed of TGT (tRNA guanine transglycosylase) and Qv1 (queuine tRNA ribosyltransferase domain containing 1). Both these proteins are associated with the mitochondria (Boland et al., 2009; Chen et al., 2010).

Although queuosine is found in almost all eukaryotic organisms, with the exception of Baker's yeast, its true physiological purpose has yet to be understood. Our studies have shown that transgenic animals made deficient in queuosine (i.e. TGT knockouts) have abnormal tyrosine production through decreased levels of tetrahydrobiopterin (BH4) cofactor. This occurs from a build-up of oxidised BH4 (Rakovich et al, 2011), shown on the diagram as 7,8 dihydrobioipterin (BH2). The causes of this effect are still under investigation.