Research   
(1) Functional chromosome ends, or telomeres, are essential for cell survival. Telomere function is maintained by (i) telomeric shelterin proteins that mediate a protective cap structure formation, and (ii) telomere lengthening, either by the enzyme telomerase, or a recombination-based mechanism (ALT). Non-functional telomeres arise due to telomere shortening or to cap alterations, and activate DNA damage checkpoints, and cell senescence or death. Non-functional telomeres may contribute to the development of aging phenotypes, such as vascular disease, poor wound healing, and immunosenescence. In the genetic syndrome dyskeratosis congenita, caused by defects in the telomerase or telomere complexes, telomere shortening is accelerated, and patients have premature onset of several age-related disorders and early death. Telomerase is active in ~85% of tumors, but weakly in primary cells, thus it is an attractive target for cancer cell-specific therapy.
 
My lab is pursuing projects to identify and characterize unique determinants of telomerase and telomere function, including determinants of enzyme processivity, telomerase domains mediating recruitment to telomeres, alternatively spliced telomerase variants, telomerase associated proteins, and post-translational modifications of telomerase components. Understanding the regulation of cell survival and tumorigenesis by telomere maintenance and telomerase will lead to the identification of targets with potential therapeutic applications to prevent age- or disease-related cell death. Specific and effective therapeutic approaches to inhibit telomerase in tumor cells will include strategies that target distinct telomerase regulatory domains, alternatively-spliced telomerase variants, or associated proteins.

(2) Targeting telomerase has at least two limitations. First, during telomerase inhibition, tumour cells proliferate for numerous divisions in a telomere length-dependent fashion until telomeres shorten sufficiently to obtain anti-proliferative effects. Second, telomerase inhibition does not target ALT cancer cells (10-15% of tumours and 20-40% of mesenchymal tumours). In principle, both these limitations can be circumvented by targeting telomere function. Telomere protective cap alterations elicit DNA damage checkpoint activation and anti-proliferative phenotypes immediately rather than in a delayed cell division-dependent telomere shortening fashion typical of telomerase inhibition. Moreover, since a protective cap is essential for cell survival telomere disruption can also target ALT cells. Recombination-based telomere maintenance may also be a potential resistance mechanism in response to telomere uncapping or chemotherapeutics.

My lab is interested in understanding the molecular mechanisms that mediate telomeric recombination and ALT regulation. Our studies investigate the hypotheses that i) the induction of telomere uncapping is a novel and valid anti-cancer strategy, ii) telomeric recombination is a mechanism of resistance to telomere uncapping and chemotherapeutics and iii) telomeric recombination and ALT are regulated by posttranslational modification pathways.

(3) Telomere integrity can also be compromised via telomere disruption by G-quadruplex ligands. Such ligands typically stabilize the G-quadruplex structures that can form at G-rich telomeres where four guanines are held together in a planar arrangement by a Hoogsteen hydrogen bonded array. These structures are poor substrates for telomerase and several G-quadruplex ligands have been reported to mediate antiproliferative responses in cancer cells. While some ligands can induce telomere shortening, rapid antiproliferative effects have also been reported.

In collaboration with the groups of Drs. Hanadi Sleiman and Nicolas Moitessier at McGill University we are evaluating ligands with increase binding affinity and selectivity to the G-quadruplex substrate. Specifically, our group is testing ligands in vitro for telomerase inhibition and in cells for antiproliferative effects. Our studies investigate the mechanisms mediating the antiproliferative effects (DNA damage at telomeres, apoptosis, senescence). Antiproliferative effects observed with previously reported G-quadruplex ligands appear to be restricted to cancer cells, suggesting that the telomere cap may differ in cancer cells versus normal cells. To validate these molecules, their anti-tumor activity in a mouse tumor model will be assessed.
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