Telomere-independent functions of telomerase in nuclei, cytoplasm, and mitochondria

Abstract

Telomerase canonical activity at telomeres prevents telomere shortening, allowing chromosome stability and cellular proliferation. To perform this task, the catalytic subunit (telomerase reverse transcriptase, TERT) of the enzyme works as a reverse transcriptase together with the telomerase RNA component (TERC), adding telomeric repeats to DNA molecule ends. Growing evidence indicates that, besides the telomeric-DNA synthesis activity, TERT has additional functions in tumor development and is involved in many different biological processes, among which cellular proliferation, gene expression regulation, and mitochondrial functionality. TERT has been shown to act independently of TERC in the Wnt-β-catenin signaling pathway, regulating the expression of Wnt target genes, which play a role in development and tumorigenesis. Moreover, TERT RNA-dependent RNA polymerase activity has been found, leading to the genesis of double-stranded RNAs that act as precursor of silencing RNAs. In mitochondria, a TERT TERC-independent reverse transcriptase activity has been described that could play a role in the protection of mitochondrial integrity. In this review, we will discuss some of the extra-telomeric functions of telomerase.

Keywords: RNA interference; TERT; apoptosis; cancer; mitochondria; telomerase; telomere; transformation.

FIGURE 1

Schematic representation of multiple TERT functions. In the nucleus, TERT can elongate telomeres binding to TERC; binding to BRG1, it can work as a coactivator of the Wnt pathway and regulate gene expression; finally, silencing experiments in somatic cells showed that TERT is involved in chromatin organization and DNA-damage response. In mitochondria, TERT plays a role in stress response, apoptosis, and in the maintenance of mitochondrial fitness; moreover, it can interact with RNAs other than TERC acquiring an additional RNA transcriptase activity or an RNA-dependent RNA polymerase activity. This last activity seems to lead the production of siRNAs that are involved in post-transcriptional gene expression regulation.