Troy Harkness

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Troy Harkness

Ph.D., University of Alberta

Adjunct Professor
Laboratory: 320 Heritage Medical Research Centre
Telephone: 780-492-1523
taharkne@ualberta.ca

 

RESEARCH INTERESTS

Our research interests are focused on using the brewing yeast as a model to characterize molecular and genetic mechanisms that regulate longevity. Since the molecular hallmarks of aging, such as genomic instability, altered nutrient and stress sensing, and epigenetic alterations are conserved from yeast to humans, we expect that observations made using yeast will apply to human cells. Furthermore, the proteins involved in maintaining these processes are also evolutionarily conserved. We have discovered that the large conserved ubiquitin ligase, the Anaphase Promoting Complex (APC), facilitates chromatin assembly and histone modifications, as well as stress resistance and longevity. We hypothesize that activation of the APC will increase lifespan in yeast and that this will be conserved throughout evolution. We have discovered small peptides that bind to the APC to activate the enzyme. APC activation in yeast increases stress resistance and lifespan in yeast. One peptide in particular, when expressed in the worm C. elegans and human cancer cells, increases worm lifespan and reverses drug resistant cancer cell growth in culture and in mice growing human derived tumor cells. Our current work is focused on characterizing the molecular networks impacted by APC activation.

A second project involves development of a human rapid premature aging model using yeast. We have expressed the mutant human Progerin gene in yeast. The expressed mutant protein is responsible for all premature aging phenotypes observed in children suffering from Hutchinson-Gilford Progeria Syndrome (HGSP), or Progeria. These children die at age 14 with age-related disease and age roughly 8 times faster than normal. When Progerin is expressed in yeast, we observe slowed growth, reduced lifespan and increased genomic instability. We are currently screening a yeast deletion library for deletions that reverse Progerin-induced slow growth. We expect to discover novel molecular pathways that can be used as potential therapeutics to benefit children with Progeria. We also expect that methods to reverse Progeria will also benefit the normal aging human population.

In a third project, introduced above, we use human cancer cells resistant to therapy as our yeast translational model. One project is focused on the discovery of proteins involved in the development of multiple drug resistance (MDR). In a second project, we treat MDR breast cancer cells with APC activator chemicals and our novel peptide to determine the function of APC activation on cancer cells. APC activation resensitizes MDR cells to chemotherapy both in vitro and in a mouse in vivo model. To gain insight into how this works we have performed kinome analyses and SILAC studies to identify differentially regulated kinase pathways and differentially expressed proteins.

We are currently accepting students interested in contributing to these projects.

 

Selected Publications

  1. Arnason, TG, MacDonald-Dickinson, V, Davies*, JF, Lobanova, L, Gaunt, C, Trost, B, Waldner*, M, Baldwin, P, Borrowman, D, Marwood, H, Gillespie, ZE, Vizeacoumar, FS, Vizeacoumar, FJ, Eskiw, CH, Kusalik, A, and, Harkness. & TAA (2022). Activation of the Anaphase Promoting Complex reverses multiple drug resistant cancer. Cancers, 14: 4215.
  2. Sarah, Moradi-Fard., Aditya, Mojumdar., Megan, Chan., Troy, A A Harkness. & Jennifer, A Cobb. (2021). Smc5/6 in the rDNA modulates lifespan independently of Fob1​. Aging Cell, 20(6): e13373.
  3. Khawaja, A., Belak, Z., Eskiw, C. & Harkness, T. (2020). High-Throughput Rapid Yeast Chronological Lifespan Assay. Methods in Molecular Biology, 2196: 229-233.
  4. VanGenderen, C., Harkness, TAA. & Arnason, TG. (2020). The role of Anaphase Promoting Complex activation, inhibition and substrates in cancer development and progression. Aging, 12(15): 15818-15855.
  5. Almendáriz-Palacios, C., Gillespie, ZE., Janzen, M., Martinez, V., Bridger, JM., Harkness, TAA., Mousseau, DD. & Eskiw, CH. (2020). The Nuclear Lamina: Protein Accumulation and Disease. Biomedicines, 8(7): 188.
  6. Belak, Z, Harkness, T, Eskiw & C (2018). A rapid, high-throughput method for determining chronological lifespan in budding yeast.. Journal of Biological Methods, 5: e106.
  7. Hu, S., Tomoiaga, A., Postnikoff, S., Harkness, T., Seol, J., Xia, B., Li, W., Chen, K. & Tyler, J. (2018). Ssd1 and Gcn2 suppress global translational efficiency in replicatively aged yeast, while their activation in young cells extends lifespan. eLife.. eLlife, 7: pii: e35551..
  8. Harkness, T. (2018). Activating the Anaphase Promoting Complex to Enhance Genomic Stability and Prolong Lifespan.. International Journal of Molecular Sciences, 19(7 ): pii: E1888.
  9. Ghavidel., A., Baxi, K., Prusinkiewicz, M., Swan, C., Belak, Z., Eskiw, C., Carvalho, C. & Harkness, T. (2018). Rapid Nuclear Exclusion of Hcm1 in Aging Saccharomyces cerevisiae Leads to Vacuolar Alkalization and Replicative Senescence. G3: Genes, Genomes, Genetics, 8(5): 1579-1592.
  10. Davies, G., Lobanova, L., Dawicki, W., Groot, G., Gordon, J., Bowen, M., Harkness, T. & Arnason, T. (2017). Metformin inhibits the development, and promotes the resensitization, of treatment-resistant breast cancer. PLOS One, 12(12): e0187191..
  11. Baxi, K., Ghavidel, A., Waddell, B., Harkness, T. & Carvalho, C. (2017). Regulation of Lysosomal Function by the DAF-16 Forkhead Transcription Factor Couples Reproduction to Aging in Caenorhabditis elegans.. Genetics,
  12. Kakish, J., Allen, K., Harkness, T., Krol, E. & Lee, J. (2016). Novel Dimer Compounds That Bind α-Synuclein Can Rescue Cell Growth in a Yeast Model Overexpressing α-Synuclein. A Possible Prevention Strategy for Parkinson’s Disease.. ACS Chemical Neuroscience, 7(12): 1671-1680.
  13. Jiao, R., Lobanova, L., Waldner, A., Fu, A., Xiao, L., Harkness, T. & Arnason, T. (2016). The ubiquitin-conjugating enzyme, Ubc1, indirectly regulates SNF1 kinase activity via Forkhead-dependent transcription.. Microbial Cell, 3(11 ): 540-553.
  14. Li, Q., Shi, X., Ye, S., Wang, S., Chan, R., Harkness, T. & Wang, H. (2016). A short motif in Arabidopsis CDK inhibitor ICK1 decreases the protein level, probably through a ubiquitin-independent mechanism. Plant Journal,
  15. Malo, M., Postnikoff, S., Arnason, T. & Harkness, T. (2016). Mitotic degradation of yeast Fkh1 by the Anaphase Promoting Complex is required for normal longevity, genomic stability and stress resistance.. Aging, 8(4): 810-30.

 

Laboratory Members

Reseacrh Associate
Spike Postnikoff; spostnik@ualberta.ca

Graduate Students
Mathew Lubachowski (PhD; lubachow@ualberta.ca),
Marina Beshara (PhD; beshara1@ualberta.ca),
Rachel Harris (PhD; reh985@mail.usask.ca)