A Single-Cell Screening Platform for Telomerase Modulators
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About this Class
Telomerase counteracts telomere shortening in dividing cells and is reactivated in ~90% of human cancers, while its insufficiency underlies stem cell failure disorders such as dyskeratosis congenita and pulmonary fibrosis. Despite decades of research, no scalable cell-based assay has existed to measure telomerase activity, limiting drug discovery efforts targeting this enzyme. My lab has developed the inducible Telomerase Activity Probe (iTAP), a single-cell assay based on conditional expression of a mutant telomerase RNA template in mouse embryonic stem cells. Cells expressing this mutant template incorporate variant telomeric repeats that can be detected in situ by FISH, providing a direct, single-cell readout of telomerase activity. We show that iTAP signal is telomerase-dependent, sensitive to loss of telomerase activity, and compatible with high-throughput imaging workflows. Using this platform, we aim to identify both inhibitors and activators of telomerase activity from chemical libraries. This approach has the potential to expand the currently limited pipeline of telomerase-targeted therapeutics for cancer and telomere-related degenerative diseases.