Telomerase activity is essential for human cancer cells in order to maintain telomeres and provide unlimited proliferation potential
and cellular immortality. However, additional non-telomeric roles emerge for the telomerase protein TERT that can impact tumourigenesis
and cancer cell properties. This review summarises our current knowledge of non-telomeric functions of telomerase in human
cells, with a special emphasis on cancer cells.
Non-canonical functions of telomerase can be performed within the nucleus as well as in other cellular compartments. These telomereindependent
activities of TERT influence various essential cellular processes, such as gene expression, signalling pathways, mitochondrial
function as well as cell survival and stress resistance. Emerging data show the interaction of telomerase with intracellular signalling
pathways such as NF-κB and WNT/β-catenin; thereby contributing to inflammation, epithelial to mesenchymal transition (EMT) and
cancer invasiveness. All these different functions might contribute to tumourigenesis, and have serious consequences for cancer therapies
due to increased resistance against damaging agents and prevention of cell death.
In addition, TERT has been detected in non-nuclear locations such as the cytoplasm and mitochondria. Within mitochondria TERT has
been shown to decrease ROS generation, improve respiration, bind to mitochondrial DNA, increase mitochondrial membrane potential
and interact with mitochondrial tRNAs. All these different non-telomere-related mechanisms might contribute towards the higher resistance
of cancer cells against DNA damaging treatments and promote cellular survival. Understanding these different mechanisms and
their complexity in cancer cells might help to design more effective cancer therapies in the future.