Research Progress on G-Quadruplexes in Human Telomeres and Human Telomerase Reverse Transcriptase (hTERT) Promoter

Abstract

The upregulation telomerase activity is observed in over 85-90% of human cancers and provides an attractive target for cancer therapies. The high guanine content in the telomere DNA sequences and the hTERT promoter can form G-quadruplexes (G4s). Small molecules targeting G4s in telomeres and hTERT promoter could stabilize the G4s and inhibit hTERT expression and telomere extension. Several G4 ligands have shown inhibitory effects in cancer cells and xenograft mouse models, indicating these ligands have a potential for cancer therapies. The current review article describes the concept of the telomere, telomerase, and G4s. Moreover, the regulation of telomerase and G4s in telomeres and hTERT promoter is discussed as well. The summary of the small molecules targeting G4s in telomeric DNA sequences and the hTERT promoter will also be shown.

Pan-cancer experimental characteristic of human transcriptional patterns connected with telomerase reverse transcriptase (TERT) gene expression status

“…For example, TERT promoter methylation is counterintuitively correlated with chromatin accessibility and TERT expression ( Salgado et al, 2020 ; Liu et al, 2023 ). Also, the formation of G-quadruplexes in the G-rich region of the promoter has a major influence on the expression of TERT , and mutations in the G-rich region of the promoter may lead to disruption of their structure which in turn strongly affects transcription factor binding and enhances TERT expression ( Gu et al, 2022 ; Pavlova et al, 2022 ).…”

“…For example, TERT can act as a modulator in NF-kB and Wnt/β-catenin signaling pathways ( Li and Tergaonkar, 2014 ). Other non-canonical functions of TERT include regulation of apoptosis, maintenance of the cellular redox homeostasis, cell proliferation, response to DNA damage, and formation of G-quadruplexes in the G-rich area of gene promoters, which can influence transcription by regulating binding of transcription factor proteins ( Fleisig et al, 2016 ; Khattar et al, 2016 ; Yuan et al, 2019 ; Rosen et al, 2020 ; Gu et al, 2022 ; Pavlova et al, 2022 ; Palamarchuk et al, 2023 ). Thus, theoretically TERT promoter mutations may also affect these and probably other processes related to TERT .…”

A Bright Horizon: Immunotherapy for Pediatric T-Cell Malignancies

“…It contains two essential subunits: human telomerase reverse transcriptase (hTERT) and the RNA subunit human telomerase RNA (hTERC). Upregulation of telomerase activity is observed in over 85–90% of human cancers; thus, targeting telomerase is an attractive approach [ 94 ].…”

Targeting the G-quadruplex structure in the hTERT promoter: In silico screening of phytocompounds and replica exchange molecular dynamics simulations

“…The hTERT promoter, which contains many G-tracts on the same DNA strand, exhibits an exceptional potential for G-quadruplex formation [14,15]. The formation of G-quadruplexes in the hTERT promoter has been shown to inhibit hTERT expression, leading to telomere shortening and senescence [16]. Recent studies have also suggested that G-quadruplexes in the hTERT promoter can play a role in hTERT activation [13][14][15].…”