|Dr. Siegfried HEKIMI|
After an early career as a professional cyclist, Siegfried Hekimi obtained a PhD degree in Biology from the University of Geneva, Switzerland in 1988. He carried out his Post Doctoral studies at the Laboratory of Molecular Biology of the Medical Research Council (MRC) of Cambridge, England. In 1992, he joined the Department of Biology at McGill, where he has been studying the molecular genetics of biological rates and aging. In 1998, Professor Hekimi founded Chronogen, a biotechnology company that, in partnership with McGill University, is applying the findings of his laboratory to the search for drugs to fight age-dependent diseases. Siegfried Hekimi is Strathcona Professor of Zoology.
Research in the Hekimi laboratory
These mutants and the corresponding genes are then characterized phenotypically, genetically and molecularly in C. elegans, as well as in mice and in cultured cells when a vertebrate homologue exists. For example, mutations of the clk-1 gene, which is necessary for the biosynthesis of the redox-active co-factor ubiquinone, result in a slow cell cycle, slow embryonic and post-embryonic development, slow behaviors such as locomotion, defecation and pumping, delayed reproduction, and an increased lifespan. Several of these phenotypes appear to be the result of low levels of reactive oxygen species (ROS; also called free radicals). ROS act as toxic molecule that damage macromolecular constituents of the cell, but also function as signaling molecules that modulate the activity of classical signal transduction pathways. The clk-1 mutant phenotypes are due to the alteration of both the toxic and the signaling properties of ROS. Strikingly, most of the effects of clk-1 on ROS metabolism and lifespan are evolutionarily conserved in mouse embryonic stem cells and in mice. This conservation suggests that there are processes that determine lifespan that are shared between animals of such disparate morphologies, physiologies and ecologies as worms and mice. The reason for this might be the universal conservation of the function of small molecular weight effectors such as ubiquinone and ROS.
Seitan VC, Banks P, Laval S, Majid NA, Dorsett D, Rana A, Smith J, Bateman A, Krpic S, Hostert A, Rollins R, Erdjument-Bromage H,Tempst P, *Benard CY, Hekimi S, Newbury S, Strachan T (2006) Metazoan Scc4 homologues link sister chromatid cohesion to cell and axon migration guidance. Public Library of Science Biology 4(8): e242.
Hekimi, S (2006) How genetic analysis tests theories of animal aging. Nature Genetics 38(9): 985-91.
Branicky R., Nguyen P., Hekimi S. (2006) Uncoupling the pleiotropic phenotypes of clk-1 with tRNA missense suppressors in Caenorhabditis elegans. Molecular and Cellular Biology [in press]
Liu, X., Jiang N., Hughes B., Bigras E., Shoubridge E., Hekimi S. (2005) Evolutionary conservation of the clk-1-dependent mechanism of longevity: loss of mclk1 increases cellular fitness and lifespan in mice. Genes & Development 19: 2424-34.
Branicky R., Hekimi S. (2005) Specification of Muscle Neurotransmitter Sensitivity by a Paired-like Homeodomain Protein in C. elegans. Development 132: 4999-5009.
De Jong, L., Meng, Y., Dent, J., and Hekimi S. (2004) Thiamine pyrophosphate biosynthesis and transport in the nematode Caenorhabditis elegans. Genetics 168(2): 845-54.
Bénard, C., Kébir, H., Takagi, S., and Hekimi S. (2004) mau-2 acts cell-autonomously to guide axonal migrations in Caenorhabditis elegans. Development 31(23): 5947-58.
Jiang, N., Bénard, C., Kébir, H., Shoubridge, E., and Hekimi S. (2003) hCLK2 links cell cycle progression, apoptosis and telomere length regulation. Journal of Biological Chemistry 278(24): 21678-84.
Hihi A., Kébir H., and Hekimi S. (2003) Sensitivity of Caenorhabditis elegans clk-1 mutants to ubiquinone side-chain length reveals multiple ubiquinone-dependent processes. Journal of Biological Chemistry 277(3): 2202-6.
Shibata,Y., Branicky, R., Landaverde, I., and Hekimi S. (2003) Redox regulation of germline and vulval development in Caenorhabditis elegans. Science 302 (5651): 1779-82.
Burgess, J., Hihi, A., Bénard, C., Branicky, R., and Hekimi S. (2003) Molecular mechanism of maternal rescue in the clk-1 mutants of Caenorhabditis elegans. Journal of Biological Chemistry 278(49): 49555-62.
Hekimi, S. and Guarente, L. (2003) Genetics and the specificity of the aging process. Science 299(5611): 1351-4
Hihi, A., Gao, Y., and Hekimi, S. (2002) Ubiquinone is necessary for C. elegans development at mitochondrial and non-mitochondrial sites. ournal of Biological Chemistry 277(3): 2202-6.
Miyadera, H., Kano, K., Miyoshi, H., Ishii, N., Hekimi, S., and Kita, K. (2002) Quinones in long-lived clk-1 mutants of C. elegans. FEBS Letters 512: 33-7.
Bénard, C. and Hekimi, S. (2002) Long-lived mutants, the rate of aging, telomeres and the germline in Caenorhabditis elegans. Mech. Ageing Dev. 123(8): 869-80.
Miyadera H., Amino H., Hiraishi A., Taka H., Murayama K., Miyoshi H., Sakamoto H., Ishii A., Hekimi S., Kita K (2001) Altered quinone biosynthesis in the long-lived clk-1 mutants of Caenorhabditis elegans. Journal of Biological Chemistry 276: 7713-7716.
Jiang N., Levavasseur F., McCright B., Shoubridge E.A., Hekimi S. (2001) Mouse CLK-1 is imported into mitochondria by an unusual process that requires a leader sequence but no membrane potential. Journal of Biological Chemistry 276: 29218-29225.
Lemieux J., Lakowski, Webb A., Barnes T., Meng Y., Hekimi S. (2001) Regulation of physiological rates in Caenorhabditis elegans by a tRNA modifying enzyme in the mitochondria. Genetics 159: 147-157.
Bénard C., McCright B., Zhang Y., Felkai S., Lakowski B., Hekimi S. (2001) The C. elegans maternal-effect gene clk-2 affects developmental timing, is essential for embryonic development, encodes a protein homologous to yeast Tel2p, and is required for telomere length regulation. Development 128(20): 4045-4055.
Branicky R., Shibata Y., Feng J., Hekimi S. (2001) Suppressor analysis of clk-1 reveals that adaptation of behavior to changes in temperature is an active process in Caenorhabditis elegans. Genetics 159(3): 997-1006.
Feng J., Busssière F., Hekimi S. (2001) Mitochondrial electron transport is a key determinent of life span in Caenorhabditis elegans. Developmental Cell 1(5): 633-44.
Levavasseur F., Miyadera H., Sirois J., Tremblay M., Kita K., Shoubridge E., Hekimi S. (2001) Ubiquinone is necessary for mouse embryonic development but is not essential for mitochondrial respiration. Journal of Biological Chemistry 276(49): 46160-4
Hekimi S, Bénard C., Branicky R., Burgess J., Hihi A., *Rea S. (2001) Why Only Time Will Tell. Mech Ageing Dev 122: 571-94.
Hekimi S., Burgess J., Bussière F., Bénard C., Meng Y. (2001) Molecular Genetics of Life Span in C. elegans: Molecular diversity, physiological complexity, mechanistic simplicity. Trends in Genetics 17(12): 712-8.
Hekimi S. (2000) Crossroads of aging in the nematode Caenorhabditis elegans. In: Molecular Genetics of Aging, Hekimi S. (ed.) Springer Verlag.
Branicky R., Bénard C., Hekimi S. (2000) clk-1, Mitochondria and Physiological Rates. BioEssays 22: 48-56.
Labbé J-C., Burgess J., Rokeach L., Hekimi S. (2000) ROP-1, an RNA quality control pathway component, affects Caenorhabditis elegans dauer formation. Proceeding of the National Academy of Science of the USA 97: 13233-38
Labbé J-C., Hekimi S., Rokeach L. (1999) Assessing the function of the Ro RNP complex using Caenorhabditiselegans as a biological tool. Biochem Cell Biol. 77: 349-354.
Felkai S., Ewbank J., Lemieux J., Labbé J-C., Brown G., Hekimi S. (1999) Control of respiration behavior and aging by the physiological clock gene clk-1. EMBO J 18(7): 1783-1792.
Whitfield C.W., Benard C., Barnes T., Hekimi S., Kim S.K. (1999) Basolateral localization of the C. elegans EGF receptor in epithelial cells by the PDZ protein LIN-10. Molecular Biology of the Cell 10(6): 2087-100.