Mechanisms of human telomerase reverse transcriptase (hTERT) regulation: clinical impacts in cancer

Abstract

BackgroundLimitless self-renewal is one of the hallmarks of cancer and is attained by telomere maintenance, essentially through telomerase (hTERT) activation. Transcriptional regulation of hTERT is believed to play a major role in telomerase activation in human cancers.Main bodyThe dominant interest in telomerase results from its role in cancer. The role of telomeres and telomere maintenance mechanisms is well established as a major driving force in generating chromosomal and genomic instability. Cancer cells have acquired the ability to overcome their fate of senescence via telomere length maintenance mechanisms, mainly by telomerase activation.hTERT expression is up-regulated in tumors via multiple genetic and epigenetic mechanisms including hTERT amplifications, hTERT structural variants, hTERT promoter mutations and epigenetic modifications through hTERT promoter methylation. Genetic (hTERT promoter mutations) and epigenetic (hTERT promoter methylation and miRNAs) events were shown to have clinical implications in cancers that depend on hTERT activation. Knowing that telomeres are crucial for cellular self-renewal, the mechanisms responsible for telomere maintenance have a crucial role in cancer diseases and might be important oncological biomarkers. Thus, rather than quantifying TERT expression and its correlation with telomerase activation, the discovery and the assessment of the mechanisms responsible for TERT upregulation offers important information that may be used for diagnosis, prognosis, and treatment monitoring in oncology. Furthermore, a better understanding of these mechanisms may promote their translation into effective targeted cancer therapies.ConclusionHerein, we reviewed the underlying mechanisms of hTERT regulation, their role in oncogenesis, and the potential clinical applications in telomerase-dependent cancers.

TheSaccharomyces cerevisiaeHrq1 and Pif1 DNA helicases synergistically modulate telomerase activityin vitro

“…Hrq1 also caused a stalling event at T25, but this effect was weaker than that observed with Pif1 ( Fig. 3A lanes [5][6][7][8]. Unlike Pif1, however, Hrq1 caused an increase in the amount of signal (i.e., decreased processivity) at positions T28 and T30 (Fig.…”

“…Telomerase regulation can occur by many methods. For instance, the transcription of human TERT can be altered genetically and epigenetically in cancers, leading to upregulation of telomerase activity (5). Similarly, the transcription of genes encoding telomerase components and telomerase activity itself can be up-or downregulated by various dietary compounds (6).…”

The Solo Play of TERT Promoter Mutations

“…Telomeres are tandem repeats of TTAGGG up to 15 kb long in humans. Together, telomeres and the shelterin complex protect chromosomal ends and preserve genomic DNA integrity [1][2][3][4]. Telomeres are shortened with each cell division.…”

“…Cancer cells circumvent replicative telomere shortening by stabilizing them [6] through one of two mechanisms: reactivation of telomerase, the enzyme that extends telomeres (85-90% of cancers) [7][8][9][10], or homologous recombination between sister chromatids, a phenomenon termed alternative lengthening of telomeres (ALT) (3-10% of cancers) [10][11][12]. Telomerase is a ribonuclear holoenzyme composed of an RNA template (TERC) and a reverse transcriptase catalytic subunit (TERT) [1][2][3][4]13]. TERT is silent in most somatic cells, and is reactivated in cancer cells, endowing them with unrestricted proliferation capacity [6,[14][15][16].…”

The impact of telomere shortening on human hippocampal neurogenesis: Implications for cognitive function and psychiatric disorder risk

“…To complement this finding, we confirmed that telomere shortening was likely being driven by the end-replication problem, as opposed to changes to the telomerase enzyme (another critical telomere regulator) during passaging. hTERT codes for the catalytic subunit of the telomerase enzyme and is tightly controlled, and closely associated with enzyme activity (67). We performed a quantitative PCR to assess differences in the expression of telomerase reverse transcriptase (hTERT) in old and young cell, and found consistently low levels of hTERT expression, which did not differ between groups (P > 0.05); see Supplementary Information, S6.…”