Queuine tRNA modification: The tRNA of almost all eukaryotic organisms including yeast, fungi, algea, plants and mammals are modified with queuine, a micronutrient that is exclusively produced by bactieria. The means by which eukaryotes use queuine and its physiological role has been a major focus for my laboratory for over 10 years. Our group was the first to identify the eukaryotic enzymes responsible for inserting queuine into transfer RNA, showing that the enzymes localize to the mitochondria. Subsequently, by knocking out the catalytic subunit of the enzyme, we could show that the absence of queuine in tRNA disrupts the ability for animals to replenish tetrahydrobiopterin, which is an essential cofactor for biogenic neurotransmitter production. Given the unique nature of the queuine incorporation mechanism (i.e. a singular pathway and a metabolically unique substrate), we explored the potential of exploiting this pathway as a novel therapeutic approach to controlling protein translation and thereby limiting the uncontrolled immune response characteristic of autoimmune diseases. Through collaboration with Prof. Stephen Connon and Dr. J. Mike Southern, the culmination of this work was the development of a specific queuine analogue (NPPDAG) that has an unprecedented ability to treat the mouse model of multiple sclerosis. Our groups are pursuing academic and commercial avenues to understand the queuine tRNA pathway in greater detail.

Micronutrients and metabolism: I have a longstanding interest in micronutrients and metabolism. Selenium is an essential compound of the metazoan diet and is required for the activity of 25 proteins in humans, in the form of the amino acid selenocysteine. The majority of selenoproteins have key roles in protection against oxidative stress. By creating knockout, conditional and promoter disruption transgenic animals for the unique transfer RNA carrier of selenocysteine we were able to demonstrate the essential role of selenium in protection against oxidative stress and the compensatory role that the Nrf2 transcription factors plays under conditions of selenium deprivation. More recently, in collaboration with the O’Neill group in Trinity College Dublin, we showed that the natural metabolite succinate is an important mediator of inflammatory responses through its ability to regulate the prototypical inflammatory cytokine IL1b. And in collaboration with the Nakajima group in Yamagata University, we could show that the oral administration of the heme-precursor aminolevulinic acid can function to limit hyperglycemia and insulin resistance in diabetes. Other recently completed projects in our group have explored the effects of select micronutrients on human fertility.

Technologies: The lab currently has two key research focuses, developing queuine based therapeutics and studying the causes and treatment of human infertility. In addition, our lab provides animal and cell-based transgenic services to research groups throughout Ireland. As a result, our activities require a range of technologies including Oxygraph, Seahorse, NMR, recombinant protein expression, FPLC, HPLC, flow cytometry, CASA, IVF, rederivation and CRISPR/Cas9.

1. Jantsch MF, Quattrone A, O’Connell M, Helm M, Frye M, Macias-Gonzales M, Ohman M,
Ameres S, Willems L, Fuks F, Oulas A, Vanacova S, Nielsen H, Bousquet-Antonelli
C, Motorin Y, Roignant JY, Balatsos N, Dinnyes A, Baranov P, Kelly V, Lamm A,
Rechavi G, Pelizzola M, Liepins J, Holodnuka Kholodnyuk I, Zammit V, Ayers D,
Drablos F, Dahl JA, Bujnicki J, Jeronimo C, Almeida R, Neagu M, Costache M,
Bankovic J, Banovic B, Kyselovic J, Valor LM, Selbert S, Pir P, Demircan T,
Cowling V, Schäfer M, Rossmanith W, Lafontaine D, David A, Carre C, Lyko F,
Schaffrath R, Schwartz S, Verdel A, Klungland A, Purta E, Timotijevic G, Cardona
F, Davalos A, Ballana E, O Carroll D, Ule J, Fray R. Positioning Europe for the
EPITRANSCRIPTOMICS challenge. RNA biology. 2018; 15(6):829-831. PubMed [journal]
PMID: 29671387

2. Saitoh S, Okano S, Nohara H, Nakano H, Shirasawa N, Naito A, Yamamoto M, Kelly
VP, Takahashi K, Tanaka T, Nakajima M, Nakajima O. 5-aminolevulinic acid (ALA)
deficiency causes impaired glucose tolerance and insulin resistance coincident
with an attenuation of mitochondrial function in aged mice. PloS one. 2018;
13(1):e0189593. PubMed [journal] PMID: 29364890, PMCID: PMC5783358

3. Varghese S, Cotter M, Chevot F, Fergus C, Cunningham C, Mills KH, Connon SJ,
Southern JM, Kelly VP. In vivo modification of tRNA with an artificial nucleobase
leads to full disease remission in an animal model of multiple sclerosis. Nucleic
acids research. 2017; 45(4):2029-2039. PubMed [journal] PMID: 28204548, PMCID:
PMC5389723

4. Fergus C, Barnes D, Alqasem MA, Kelly VP. The queuine micronutrient: charting a
course from microbe to man. Nutrients. 2015; 7(4):2897-929. PubMed [journal]
PMID: 25884661, PMCID: PMC4425180

5. Tannahill GM, Curtis AM, Adamik J, Palsson-McDermott EM, McGettrick AF, Goel G,
Frezza C, Bernard NJ, Kelly B, Foley NH, Zheng L, Gardet A, Tong Z, Jany SS, Corr
SC, Haneklaus M, Caffrey BE, Pierce K, Walmsley S, Beasley FC, Cummins E, Nizet
V, Whyte M, Taylor CT, Lin H, Masters SL, Gottlieb E, Kelly VP, Clish C, Auron
PE, Xavier RJ, O’Neill LA. Succinate is an inflammatory signal that induces IL-1β
through HIF-1α. Nature. 2013; 496(7444):238-42. NIHMSID: NIHMS565941 PubMed
[journal] PMID: 23535595, PMCID: PMC4031686

6. Psg22 null mouse embryos develop normally under normoxic and hypoxic conditions
of pregnancy.
Williams JM, Bezak T, Das M, Ning Z, Lucking EF, Kelly VP, Harrison P, Young P,
O’Connell MJ, Dockery P, O’Halloran KD, Moore T.
Science Matters. 2016; 10(19185).
My Bibliography [journal]

7. Rakovich T, Boland C, Bernstein I, Chikwana VM, Iwata-Reuyl D, Kelly VP.
Queuosine deficiency in eukaryotes compromises tyrosine production through
increased tetrahydrobiopterin oxidation. The Journal of biological chemistry.
2011; 286(22):19354-63. PubMed [journal] PMID: 21487017, PMCID: PMC3103313

8. Kawatani Y, Suzuki T, Shimizu R, Kelly VP, Yamamoto M. Nrf2 and selenoproteins
are essential for maintaining oxidative homeostasis in erythrocytes and
protecting against hemolytic anemia. Blood. 2011; 117(3):986-96. PubMed [journal]
PMID: 20978266

9. Chen YC, Kelly VP, Stachura SV, Garcia GA. Characterization of the human
tRNA-guanine transglycosylase: confirmation of the heterodimeric subunit
structure. RNA (New York, N.Y.). 2010; 16(5):958-68. PubMed [journal] PMID:
20354154, PMCID: PMC2856889

10. Boland C, Hayes P, Santa-Maria I, Nishimura S, Kelly VP. Queuosine formation in
eukaryotic tRNA occurs via a mitochondria-localized heteromeric transglycosylase.
The Journal of biological chemistry. 2009; 284(27):18218-27. PubMed [journal]
PMID: 19414587, PMCID: PMC2709355

11. Suzuki T, Kelly VP, Motohashi H, Nakajima O, Takahashi S, Nishimura S, Yamamoto
M. Deletion of the selenocysteine tRNA gene in macrophages and liver results in
compensatory gene induction of cytoprotective enzymes by Nrf2. The Journal of
biological chemistry. 2008; 283(4):2021-30. PubMed [journal] PMID: 18039655

12. MacLeod AK, Kelly VP, Higgins LG, Kelleher MO, Price SA, Bigley AL, Betton GR,
Hayes JD. Expression and localization of rat aldo-keto reductases and induction
of the 1B13 and 1D2 isoforms by phenolic antioxidants. Drug metabolism and
disposition: the biological fate of chemicals. 2010; 38(2):341-6. PubMed
[journal] PMID: 19920056