Telomerase reverse transcriptase moonlights: Therapeutic targets beyond telomerase

Abstract

Telomeres, the repetitive sequences at chromosomal ends, protect intact chromosomes. Telomeres progressively shorten through successive rounds of cell divisions, and critically shortened telomeres trigger senescence and apoptosis. The enzyme that elongates telomeres and maintains their structure is known as telomerase. The catalytic subunit of this enzyme (telomerase reverse transcriptase [TERT]) is expressed at a high level in malignant cells, but at a very low level in normal cells. Although telomerase activity was long believed to be the only function of TERT, emerging evidence indicates that TERT plays roles beyond telomeres. For example, TERT contributes to stem cell maintenance and cell reprogramming processes in a manner independent of its canonical function. Even some types of splice variants that lack the telomerase catalytic domains exhibit the functions in a manner that does not depend on telomerase activity. We recently demonstrated that the RNA‐dependent RNA polymerase (RdRP) activity of TERT is involved in regulation of gene silencing and heterochromatic transcription. Moreover, TERT RdRP activity is mediated by a newly identified complex, distinct from the authentic telomerase complex, that plays a role in cancer stem cells in a telomere maintenance independent manner. TERT has attracted interest as a molecular target for anticancer treatment, but previous efforts aimed at developing novel therapeutic strategies focused only on the canonical function of TERT. However, accumulating evidence about the non‐canonical functions of TERT led us to speculate that the functions other than telomerase might be therapeutic targets as well. In this review, we discuss the non‐canonical functions of TERT and their potential applications for anticancer treatment.

RNA interference mediated downregulation of human telomerase reverse transcriptase (hTERT) in LN18 cells

“…Flow cytometry studies showed that, at 48 h post-transfection the number of total apoptotic cells was significantly increased. There are several pathways involved in hTERT mediated apoptosis; this can be telomerase dependent pathways such as Bax/Bcl-2 pathway, PI3 k/Akt pathway (Wang et al 2012;Shi et al 2014) or telomerase independent pathways (non-canonical) like DNAdamage repair, WNT/b-catenin signaling, NF-jB signaling and regulation of mitochondrial activity (Chiodi and Mondello 2011;Maida and Masutomi 2015). However, our results cannot conclude whether the apoptosis is mediated through hTERT dependent or independent pathway.…”

“…Telomerase consists of telomerase RNA (hTR) and the catalytic component human telomerase reverse transcriptase (hTERT) for telomeric DNA synthesis. Evidence from the previous studies shows that, beyond the telomeric DNA synthesis activity, TERT is involved in several other functions including tumor development, cell proliferation, gene expression regulation and mitochondrial functionality (Chiodi and Mondello 2011;Maida and Masutomi 2015). It also plays a major role in stem cell maintenance and cell reprogramming processes.…”

“…It also plays a major role in stem cell maintenance and cell reprogramming processes. Furthermore, TERT RNA-dependent RNA polymerase activity (RdRP) is involved in gene regulation and heterochromatic transcription (Maida and Masutomi 2015). Telomerase is usually inactive in somatic cells but remains active in germ cells, embryonic stem cells and tumor cells (Kim et al 1994;Shay and Bacchetti et al Shay and Bacchetti 1997;Cowell 1999).…”

The role of the tumour microenvironment in immunotherapy

“…Cancer cells frequently activate the expression of telomerase reverse transcriptase (hTERT) to maintain telomere ends of DNA (Maida & Masutomi 2015). The ability of hTERT peptides to induce cancer cell-specific cytotoxic T cell activity was explored in the phase III TeloVac study.…”

An Overview of Genetic Polymorphism and Lung Cancer Risk

“…There are conflicting results regarding the association between the TERT SNPs and telomere length in leukocytes [28,30]. However, variants in the TERT promoter region (rs2853669 and rs2735940) and intron 4 (rs10069690) are likely to affect telomere length in leucocytes or noncancerous tissues [31,32]. The rs2853669 SNP is associated with ADC risk (rs2853669, odds ratio (OR) = 1.38); however, neither rs2853669 nor rs10069690 is statistically associated with ADC risk in the Japanese population (OR=1.06 and 1.07, respectively) [11].…”