Karim Mekhail

Karim Mekhail PhD
Co-Coordinator Specialist Program in Pathobiology and Co-Associate Chair Undergraduate Life Science Education
Associate Professor
Department of Laboratory Medicine & Pathobiology
Karim Mekhail
Contact Info
T: (416) 946-8132
Website
Location
MaRS Centre
661 University Ave.
MaRS Centre West Tower, Room 1513
Toronto, ON, M5G 1M1
Appointment Status Primary
Research Interests
Molecular & Cell Biology, Human Development & Aging

Research/Teaching

Research Synopsis

The ultimate goal of our research group is to chart and understand how various molecular networks maintain genome stability and human health.

Our research can be categorized into two themes:

  1. the ultimate goal of deciphering how the genome is non-randomly arranged within the nucleus and understand the impact of this order on diseases such as cancer and premature aging
  2. we aim to reveal how cells regulate non-coding RNA moelcules in order to maintain genome stability and prevent various neurodegenetive diseases.

Non-random subnuclear DNA organization in genome stability and human health

This first of our two main lab research themes aims to decipher the impact of non-random positioning of DNA loci within the nucleus on fundemental cellular processes as well as various physiological and pathological settings.

What defines preferred DNA locus positions within the nucleus and how this affects genome stability and function is unclear. Gain or loss of chromosomal regions, which can result in genome instability and diseases such as cancer, are commonly instigated by repetitive DNA sequences as these are abundant in eukaryotes and often trigger chromosome restructuring.

Our lab has made a series of findings that are helping us better understand the establishment and function of non-random genome organization within various contexts.

We have discovered how interactions between chromosomal complexes and inner nuclear membrane (INM) proteins organize several chromosomal regions characterized by repetitive DNA sequences at the nuclear envelope in order to maintain silent chromatin, genome stability and cellular lifespan.

We are actively engage in research that will help us understand the role of this spatial organization in various fundemental cellular processes including DNA repair, recombination, and replication.

This work is unlocking many of the secrets of DNA organization in the nucleus.

Understanding the role of this genomic order is also shedding light on the pathobiology of several human diseases such as cancer, muscular dystrophy, premature aging, and cardiac malfunction.

Our research relies primarily on powerful yeast genetic models and also various mammalian cell systems including human stem cells.

Intergenic non-coding RNA in chromosome instability and human disease

The classical view of the flow of genetic information has been from DNA to RNA to proteins. The latter being the ultimate effector proteins.

More recently, so called non-coding RNA molecules that do not lead to proteins have also been found to be able to directly affect the cell by impacting DNA, other RNAs, and proteins.

Such non-coding RNAs can have a positive or negative impact on the cell.

We are actively engaged in characterizing novel and conserved cellular pathways that help cells maximize the positive and limit the negative impact of non-coding RNA molecules.

Characterization of these processes in both yeast and human cells is helping us decipher pathobiological processes underlying a number of neurodegenerative diseases.

This research is also helping us identify completely new avenues for therapeutic intervention for multiple so far incurable brain diseases.

Publications and Awards

View PubMed search of this faculty member's recent publications.

Recent Publications

Chung, K.C., Chan, J.N., Strecker, J., Zhang, W., Ebrahimi-Ardebili, S., Lu, T., Abraham, K.J., Durocher, D. and Mekhail, K. (2015) Perinuclear tethers license telomeric DSBs for a broad kinesin- and NPC-dependent DNA repair process. Nature Communications. 6:7742 doi: 10.1038/ncomms8742

Szafranski, K., Abraham, K.J., and Mekhail, K. (2015) Non-coding RNA in neural function, disease, and aging. Front. Genet. 6(87):1-16.

Salvi, J.S. and Mekhail, K. (2015) R-loops highlight the nucleus in ALS. Nucleus 6(1):23-29.

Salvi, J.S., Chan, J.N.Y., Szafranski, K, Liu, T.T., Wu, J.D., Olsen, J.B., Khanam, N., Poon, B.P.K., Emili, A., and Mekhail, K.** (2014) Roles for Pbp1 and caloric restriction in genome and lifespan maintenance via suppression of RNA-DNA hybrids. Dev. Cell 30(2):177-191. [cover article]

Szafranski, K. and Mekhail, K. (2014) The fine line between lifespan extension and shortening in response to caloric restriction. Nucleus 5(1):56-65.

Salvi, J., Chan, J.N.Y., Pettigrew, C., Liu, T.T., Wu, J.D., and Mekhail, K.** (2013) Enforcement of a lifespan-sustaining distribution of Sir2 between telomeres, mating-type loci, and rDNA repeats by Rif1. Aging Cell 12(1):67-75.

Poon, B.P.K. and Mekhail, K. (2012) Effects of perinuclear chromosome tethers in the telomeric URA3/5FOA system reflect changes to gene silencing and not nucleotide metabolism. Front. Genet. 3(144):1-9.

Poon, B.P.K. and Mekhail, K. (2011) Cohesin and related coiled-coil domain-containing complexes physically and functionally connect the dots across the genome. Cell Cycle 10:2669-2682.

Chan, J.N.Y., Poon, B.P.K., Salvi, J., Olsen, J.B., Emili, A., and Mekhail, K.** (2011) Perinuclear cohibin complexes maintain replicative life span via roles at distinct silent chromatin domains. Dev. Cell 20:867-879.

Mekhail, K.**, and Moazed D.** (2010) The nuclear envelope in genome organization, expression, and stability. Nature Reviews Mol. Cell Biol. 11:317-328.

Tomson, B. N., Rahal, R., Reiser, V., Monje-Casas, F., Mekhail, K., Moazed, D., and Amon, A. (2009) Regulation of Spo12 Phosphorylation and Its Essential Role in the FEAR Network. Curr. Biol. 19:449-460.

Mekhail, K., Seebacher, J., Gygi, S. P., and Moazed, D. (2008) Role for perinuclear chromosome tethering in maintenance of genome stability. Nature 456:667-670.

Khacho, M., Mekhail, K., Pilon-Larose, K., Pause, A., Côté, J., and Lee, S. (2008) eEF1A is a novel component of the mammalian nuclear protein export machinery. Mol. Biol. Cell 19:5296-5308.

Khacho, M., Mekhail, K., Pilon-Larose, K., and Lee, S. (2008) Cancer-causing mutations in a novel transcription-dependent nuclear export motif of VHL abrogate oxygen-dependent degradation of HIF. Mol. Cell. Biol. 28:302-314.

Mekhail, K., Rivero-Lopez, L., Al-Masri, A., Brandon, C., Khacho, M., and Lee, S. (2007) Identification of a common subnuclear localization signal. Mol. Biol. Cell 18:3966-3977.

Mekhail, K., Rivero-Lopez, L., Khacho, M., and Lee, S. (2006) Restriction of rRNA synthesis by VHL maintains energy equilibrium under hypoxia. Cell Cycle 5:2401-2413.

Mekhail, K., Khacho, M., Carrigan, A., Hache, R. J., Gunaratnam, L., and Lee, S. (2005) Regulation of ubiquitin ligase dynamics by the nucleolus. J. Cell Biol. 170:733-744.

Smith, K., Gunaratnam, L., Morley, M., Franovic, A., Mekhail, K., and Lee, S. (2005) Silencing of epidermal growth factor receptor suppresses hypoxia-inducible factor-2-driven VHL-/- renal cancer. Cancer Res. 65:5221-5230.

Mekhail, K., Khacho, M., Gunaratnam, L., and Lee, S. (2004) Oxygen sensing by H+: implications for HIF and hypoxic cell memory. Cell Cycle 3:1027-1029.

Mekhail, K., Gunaratnam, L., Bonicalzi, M. E., and Lee, S. (2004) HIF activation by pH-dependent nucleolar sequestration of VHL. Nature Cell Biol. 6:642-647.

Gunaratnam, L., Morley, M., Franovic, A., de Paulsen, N., Mekhail, K., Parolin, D. A., Nakamura, E., Lorimer, I. A., and Lee, S. (2003) HIF activates the TGFa/EGFR growth stimulatory pathway in VHL-/- renal cell carcinoma cells. J. Biol. Chem. 278:44966-44974.