QUANTIFICATION OF TELOMERASE COMPLEX PROTEINS AND TRANSCRIPTIONAL REGULATION OF TERT

Abstract

Telomerase is reactivated in ~90% of the cancers and re-activation of hTERT gene is the key mechanism. In the first part of my study, to understand the minimum requirement for the telomerase activity as well as non-telomeric functions, I have quantified hTERT molecule and other telomerase complex molecules in cancer cells. My results indicated that there were at least ~650 hTERT molecules per cell to perform telomeric and non-telomeric functions in the cell. In the second part of my study I investigated the molecular mechanism of hTERT reactivation in cancers where hTERT expression is driven due to mutation in hTERT promoter. I investigated the epigenetic mechanisms including long-range interactions and histone marks enrichment of the mutant and wild-type hTERT promoters and identified long-range interaction between mutant hTERT promoter and T-INT1 region that reactivates hTERT transcription via recruiting active histone marks, chromatin remodeling protein BRD4 and RNA Pol2 to the promoter.