Ph.D. University of Alberta, 1992
E146 Beadle Center
Gene regulatory mechanisms: We use two fungal model organisms, Saccharomyces cerevisiae (baker’s yeast) and Candida albicans (a common opportunistic pathogen of humans) to understand how gene expression is regulated during cell and developmental biology.
Regulation of wild type gene expression by the nonsense-mediated mRNA decay pathway. Nonsense-mediated mRNA decay (NMD) is a highly conserved mRNA decay pathway that serves a surveillance mechanism by ridding cells of abnormal mRNAs. This is important because truncated proteins made from these mRNAs are potentially harmful. It also regulates the accumulation of many normal cellular mRNAs. This means that the NMD pathway serves a second, important function regulating normal gene expression. Currently we use a combination of molecular genetics and systems biology to: (1) Identify additional normal cellular mRNAs that are degraded by the NMD pathway and investigate the mechanisms targeting these mRNAs for decay; (2) Examine the evolutionary conservation of normal cellular mRNA decay by the NMD pathway.
An understanding of the regulation of wild type gene expression by the NMD pathway will provide a working model of the decay of mRNAs by specialized mRNA decay pathways. This is important because regulation of gene expression is essential for the good health of all organisms and mRNA decay is a key step in the regulation of gene expression. Despite this we still do not have a good understanding of how mRNA decay is regulated. Further, NMD is an important modulator of human genetic diseases since approximately one third of the known disease associated mutations result in abnormal mRNAs that code for truncated proteins. Currently strategies are being developed to manipulate the NMD pathway for treatment of these diseases. Therefore it is critically important that we understand how the NMD pathway also regulates wild type gene expression to identify and minimize the potential side effects of therapies that modulate NMD.
Regulation of Candida albicans morphogenesis by quorum sensing. C. albicans is the most common opportunistic fungal pathogenic of humans. It is normally found in the gastrointestinal and genitourinary tract and to a lesser extent on the skin of most people. However, given the opportunity, it can cause systemic infections where it spreads throughout the body and then forms fungal masses in the kidney, heart or brain. Ultimately systemic infections can cause death. It has the ability to grow and interconvert between different cell shapes (morphological forms). The ability to change morphological forms is regulated, in part, by the quorum sensing molecule farnesol. Farnesol is synthesized by C. albicans and it blocks morphological changes in response to most, if not all, inducers of the morphological change. Farnesol also acts as a virulence factor for systematic Candida infections in a mouse model, and the response to farnesol is unique to C. albicans because it does not block the morphological change in the other dimorphic fungal species we have tested. We are part of a multidisciplinary team studying the role of farnesol. We are determining how C. albicans interprets signaling by farnesol at the level of gene regulation and expression, and then executes this regulation through changes in cell structure, dynamics and function. We are also determining how farnesol affects the interaction between C. albicans and its host.
An understanding of how C. albicans responds to farnesol and its role in systemic infections is important because it will help us understand how this fungus controls its morphology and causes systematic infections. This, in turn, should provide a series of new targets for the design of novel drugs to treat C. albicans infections. There is a need for these drugs because the current drugs are not always very effective and this means too many patients with systemic Candida infections are still dying.
- Deliz-Aguirre, R., A. L. Atkin and B. W. Kebaara, 2011. Copper tolerance of Saccharomyces cerevisiae nonsense-mediated mRNA decay mutants. Current Genetics, In press.
- Atkin, A. L., 2011. Yeast bioinformatics and strain engineering resources. Methods in Molecular Biology, vol. 765, Strain Engineering: Methods and Protocols, Ed. J. A. Williams, Humana Press Inc., Totowa, NJ. pp 173-187.
- Johnson, B., R. Steadman, K. D. Patefield, J. J. Bunker, A. L. Atkin and P. Dussault, 2011. N-d-phosphonoacetyl-L-ornithine (PALO): A convenient synthesis and investigation of its effect on regulation of amino acid biosynthetic genes in Saccharomyces cerevisiae. Bioorg. Med. Chem. Letters. 21(8):2351-2353.
- Langford, M. L., S. Hasim, K. W. Nickerson, and A. L. Atkin, 2010. Activity and toxicity of farnesol towards Candida albicans is dependent on growth conditions. Antimicrobial Agents and Chemotherapy, 54(2):940-942.
- Langford, M. L., A. L. Atkin, and K. W. Nickerson, 2009. Cellular interactions of farnesol, a quorum-sensing molecule produced by Candida albicans. Future Microbiology 4(10):1353-1362.
- Kebaara, B.K. and A. L. Atkin, 2009. Long 3’-UTRs target wild type mRNAs for nonsense-mediated mRNA decay in Saccharomyces cerevisiae. Nucleic Acids Research, 37(9):2771-2778.
- Ghosh, S., D. H. M. L. P. Navarathna, D. D. Roberts, J. T. Cooper, A. L. Atkin, T. M. Petro, and K. W. Nickerson, 2009. Arginine induced germ tube formation in Candida albicans is essential for escape from murine macrophage cell line RAW264.7. Infection and Immunity, 77(4):1596-1605.
- Ghosh, S., B. Kebaara, A. L. Atkin, and K. W. Nickerson, 2008. Regulation of aromatic alcohol production in Candida albicans. Applied and Environmental Microbiology, 74:7211-7218.
- Kebaara, B. W., M. L. Langford, D. H. M. L. P. Navaranthna, R. Dumitru, K. W. Nickerson, and A. L. Atkin, 2008. Candida albicans Tup1 is involved in farnesol-mediated inhibition of filamentous growth induction. Eukaryotic Cell, 7:980-987.
- Dumitru, R., D. H. M. L. P. Navarathna, C. P. Semighini, C. G. Elowsky, R. V. Dumitru, D Dignard, M. Whiteway, A. L. Atkin, K. W. Nickerson, 2007. In vivo and in vitro anaerobic mating in Candida albicans. Eukaryotic Cell, 6:465-472.
- Kebaara, B. W., L. E. Nielson, K. W. Nickerson, and A. L. Atkin, 2006. Determination of mRNA half-lives in Candida albicans using thiolutin as a transcription inhibitor. Genome, 49:894-899.
- Nickerson, K. W., A. L. Atkin, and J. M. Hornby, 2006. Quorum sensing in dimorphic fungi: Farnesol and beyond, Appl. Environ. Microbiol., 72:3805-3813.
- Jensen, E. C., J. M. Hornby, N. E. Pagliaccetti, C. M. Wolter, K. W. Nickerson, and A. L. Atkin, 2006. Farnesol restores wild-type colony morphology to 96% of Candida albicans colony morphology variants recovered following treatment with mutagens. Genome, 49:346-353.
- Taylor, R., B. W. Kebaara, T. Nazarenus, A. Jones, R. Yamanaka, R. Uhrenholdt, J. P. Wendler, and A. L. Atkin, 2005. Gene set co-regulated by the Saccharomyces cerevisiae nonsense-mediated mRNA decay pathway. Eukaryotic Cell, 4(12):2066-2077.
- Mosel, D.D., R. Dumitru, J. M. Hornby, A. L. Atkin, and K. W. Nickerson, 2005. Farnesol concentrations required to block germ tube formation in Candida albicans in the presence and absence of serum. Appl. Environ. Microbiol., 71:4938-4940.
- Nazarenus, T., R. Cedarberg, R. Bell, J. Cheatle, A. Forch, A. Haifley, A. Hou, B. Kebaara, C. Shields, K. Stoysich, R. Taylor, and A. L. Atkin, 2005. Upf1p, a highly conserved protein required for nonsense-mediated mRNA decay, interacts with two nuclear pore proteins, Nup100p and Nup116p. Gene 345:199-212.
- Kebaara, B., T. Nazarenus, R. Taylor, A. Forch, and A. L. Atkin, 2003. The Upf-dependent decay of wild-type PPR1 mRNA depends on its 5’-UTR and first 92 ORF nucleotides. Nucleic Acids Res. 31:3157-3165.
- Kebaara, B., T. Nazarenus, R. Taylor, and A. L. Atkin, 2003. Genetic background affects relative nonsense mRNA accumulation in wild-type and upf mutant yeast strains. Curr. Genet. 43:171-177