Telomerase regulation: A key to inhibition?

Abstract

Telomerase has been recognized as a common factor in most tumor cells, and in turn a distinctive feature with respect to non-malignant cells. This feature has made telomerase a promising target for cancer therapy. Telomerase studies revealed that it is a multi-subunit complex possessing different levels of regulation, including control of expression, phosphorylation state, assembly and transportation to sites of activity. Thus, we emphasize that targeting telomerase expression or activity is not the only way to shorten telomeres, induce cell senescence and apoptosis. Therefore, there are multiple sites capable of allowing the modulation of its enzymatic activity. In the development of strategies based on the regulation of telomerase activity the understanding of the mechanisms regulating their subunits is essential. Based on this, in this review we summarize the current state of knowledge of some regulatory mechanisms of the components of the telomerase complex, and hypothetize their potential therapeutic application against cancer.

Telomeres and Telomere Length: A General Overview

“…The 3' end of TERC contains a conserved H/ACA domain ( Figure 5) that binds the protein complex formed by dyskerin (DKC1), nucleolar protein 10 (NOP10), non-histone protein 2 (NHP2), and encoding H/ACA ribonucleoprotein complex subunit 1 (GAR1) [17,103,104]. NOP10 and GAR1 bind to dyskerin, and NHP2 binds to the RNA directly [105]. TERC in the nucleolus assembles with TERT to form a mature telomerase complex, followed by recognition of the Cajal body (CAB) box by telomerase and telomerase cajal body protein 1 (TCAB1), which in turn recruits mature telomerase complex to Cajal body [106].…”

The Telomere/Telomerase System in Chronic Inflammatory Diseases. Cause or Effect?

“…These are the RNA component, serving as a template to the telomeric sequence, and the catalytic subunit, a reverse transcriptase synthesizing new telomeres having its own RNA as a template [ 12 , 13 ]. This way the cell can compensate for telomeric loss continuing its divisions [ 14 , 15 ]. However, since immortality is not a human trait, telomerase is not active in the majority of human mature cells and that is why most of the somatic cells eventually die, a phenomenon directly responsible for ageing [ 16 , 17 , 18 , 19 ].…”

The Telomerase Reverse Transcriptase Subunit from the Dimorphic Fungus Ustilago maydis

“…TERT subunit expression and activity have been detected in unicellular eukaryotes and metazoans. TERT can be regulated by diverse mechanisms, including both transcriptional regulation and posttranscriptional alternative mRNA splicing, multimerization, phosphorylation of the telomerase catalytic subunit and ncRNA interactions [7] – [9] . TERT gene expression and telomerase activity have been detected in immortal cells, such as cancer cell lineages and in germinal and pluripotent cells [10] – [12] ; however, in most somatic cells, the TERT gene is gradually downregulated as cellular development progresses in the metazoan life cycle, and telomerase activity eventually becomes undetectable [11] , [13] .…”