Telomerase in cancer- ongoing quest and future discoveries

Telomerase, constituted by the dynamic duo of telomerase reverse transcriptase (TERT), the catalytic entity, and an integral RNA component (TERC), is predominantly suppressed in differentiated human cells due to postnatal transcriptional repression of the TERT gene. Dysregulation of telomerase significantly contributes to cancer development via telomere-dependent and independent mechanisms. Telomerase activity is often elevated in advanced cancers, with TERT reactivation and upregulation of TERC observed in early tumorigenesis. Beyond their primary function of telomere maintenance, TERT and TERC exhibit multifaceted roles in regulating gene expression, signal transduction pathways, and cellular metabolism. The presence of the enzymatic component TERT in both the nucleus and mitochondria underscores its non-canonical roles. Cell death is prevented in TERT-upregulated cells regardless of the DNA damage events and safeguards mitochondrial DNA from oxidative damage. This highlights its protective role in cancer cells where it intersects with glucose metabolism and epigenetic regulation, shaping tumor phenotypes. Oncogenic viruses exploit various strategies to manipulate telomerase activity, aiding cancer progression. The perpetual cell proliferation facilitated by telomerase is a hallmark of cancer, making it an attractive therapeutic target. Inhibitors targeting the catalytic subunit of telomerase, nutraceutical-based compounds, and telomerase-based vaccines represent promising avenues for cancer therapy. Considering the pivotal roles played by the complete enzyme telomerase and TERT component in cancer initiation, substantial endeavors have been dedicated to unravel the mechanisms driving telomerase activation and TERT induction. This review also explores how computational modeling can be leveraged to uncover new insights in telomere research, and efficient targeted therapies.