Trinity College Dublin

Skip to main content.

Top Level TCD Links

Dr Vincent Kelly

tRNA Biology


V. Kelly photo

Dr Vincent Kelly
Assistant Professor
Phone: +353-1-896 3507
Fax: +353-1-677 2086
Email: kellyvp@tcd.ie
Location: Room 6.18, Trinity Biomedical Sciences Institute

RESEARCH INTERESTS


View audio/video clip of Dr Kelly talking about his research (mp4, 27.3MB)

Transfer RNA Modifications

Diagram 1

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.

Diagram 2

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).

Queuine in Tyrosine Biosynthesis:

pathway diagram

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.

 

 

Micronutrients & Queuine in Cancer:

Throughout my academic career I have had a keen interest in cancer and cancer prevention. My PhD research focused on dietary micronutrients known as phytochemicals which are molecules found in the diet with no calorific benefit but which have the ability to protect against cancer, such as coumarin (see figure below), ethoxyquin, and resveretrol. It is well recognised that the damage caused by by oxygen, referred to as oxidative stress, contributes significantly to aging and cancer. One of the major mechanisms used by the body to eradicate harmful oxygen molecules and the resulting damage relies on the micronutrient selenium. Using transgenic models of seleium deficiency I have previously shown how the body reponds to the increase in oxidative damage in the absence of the protective selenium mechanism.

Supplement pictures

Queuine is yet another example of a micronutrient and a curious feature of queuosine in tRNA is that it becomes deficient in cancer. This has been demonstrated for a number of solid and non-solid tumour types including lung cancer, cervical cancer and leukemia. Indeed it has been shown that patient survival is proportional to the levels of queuosine in tRNA. Our present research is investigating why queuosine deficiency occurs in cancer and the consequence that the absence of queuosine may have on tumor formation and metastasis.

 

diagram 3

 

 

The figure (left) shows the association of the TGT and Qv1 proteins to the mitochondria of HeLa cells that have been co-stained with the dye MitoTracker Red and viewed under confocal microscrope (a microscope that allows an image to be viewed in a single plane of focus)

 

 

 

 

CURRENT RESEARCH PERSONNEL

Photo of RNA Biology Group


FINANCIAL SUPPORT

Irish Cancer Society logo HRB logo Enterprise Ireland logo

 

COLLABORATORS

Dr. Mike Southern, School of Chemistry, Trinity College Dublin
Prof. Stephen Connon, School of Chemistry, Trinity College Dublin
Prof. Brian McMurry, Department of Chemistry, Trinity College Dublin
Prof. Kingston Mills, School of Biochemistry & Immunology, Trinity College Dublin
Dr. Tim Mantle, School of Biochemistry & Immunology, Trinity College Dublin
Prof. Masayuki Yamamoto, University of Tsukuba, Japan
Dr. Susumu Nishimura, University of Tsukuba, Japan

PUBLICATIONS

Publications


Last updated 12 May 2014 bbutler@tcd.ie (Email).