Project description:We report the genome wide binding of endogeneous TERT in various cell types. The binding signature is highly overlapping with RNA polymerase III components.
Project description:Telomerase reverse transcriptase (TERT) is the reverse transcriptase component of the telomeric complex, which synthesizes terminal DNA to protect chromosomal ends and to maintain genomic integrity. In melanoma, mutation in TERT promoter region is a common event and theses promoter variants have been shown to be associated with increased gene expression, decreased telomere length and poorer outcome. In this study, we determined the frequency of TERT promoter mutation in 88 Korean primary melanoma patients and aimed to see the association of TERT promoter mutation status to other major molecular features, such as BRAF, NRAS, KIT mutations and correlate with clinicopathological features. In our study, acral melanoma (n=46, 52.3%) was the most common type. Overall, TERT promoter mutation was observed in 15 cases (17%) with ten c. -124C>T altertions and five c. -146C>T alterations. None of our samples showed CC>TT mutation which is considered pathognomonic of UV induction. Among the 46 acral melanoma patients, 5 patients (10.9%) harbored TERT promoter mutation. Tumors with TERT promoter mutation showed significantly greater Breslow thickness compared to WT tumors (P=0.039). A combined analysis for the presence of TERT promoter and BRAF mutations showed that patients with both TERT promoter and BRAF mutation showed decreased survival compared with those with only TERT promoter mutation, only BRAF mutation, or without mutations in either TERT promoter or BRAF (P=0.035). Our data provides additional evidence that UV-induced TERT promoter mutation frequencies vary depending on melanoma subtype, but preserves its prognostic value.
Project description:The accumulated evidence has pointed to a key role of telomerase in carcinogenesis. As a RNA-dependent DNA polymerase, telomerase synthesizes telomeric DNA at the end of linear chromosomes, and attenuates or prevents telomere erosion associated with cell divisions. By lengthening telomeres, telomerase extends cellular life-span or even induces immortalization. Consistent with its functional activity, telomerase is silent in most human normal somatic cells while active only in germ-line, stem and other highly proliferative cells. In contrast, telomerase activation widely occurs in human cancer and the enzymatic activity is detectable in up to 90% of malignancies. Recently, hotspot point mutations in the regulatory region of the telomerase reverse transcriptase (TERT) gene, encoding the core catalytic component of telomerase, was identified as a novel mechanism to activate telomerase in cancer. This review discusses the cancer-specific TERT promoter mutations and potential biological and clinical significances.
Project description:Helicobacter pylori infection causes chronic gastritis and is the major risk factor of gastric cancer. H. pylori induces a chronic inflammation-producing reactive oxygen species (ROS) which is a source of chromosome instabilities and contributes to the development of malignancy. H. pylori also promotes DNA hypermethylation, known to dysregulate essential genes that maintain genetic stability. The maintenance of telomere length by telomerase is essential for chromosome integrity. Telomerase reverse transcriptase (TERT) is the catalytic component of telomerase activity and an important target during host-pathogen interaction. We aimed to investigate the consequences of H. pylori on the regulation of TERT gene expression and telomerase activity. In vitro, hTERT mRNA levels and telomerase activity were analysed in H. pylori-infected human gastric epithelial cells. In addition, C57BL/6 and INS-GAS mice were used to investigate the influence of H. pylori-induced inflammation on TERT levels. Our data demonstrated that, in vitro, H. pylori inhibits TERT gene expression and decreases the telomerase activity. The exposure of cells to lycopene, an antioxidant compound, restores TERT levels in infected cells, indicating that ROS are implicated in this downregulation. In vivo, fewer TERT-positive cells are observed in gastric tissues of infected mice compared to uninfected, more predominantly in the vicinity of large aggregates of lymphocytes, suggesting an inflammation-mediated regulation. Furthermore, H. pylori appears to downregulate TERT gene expression through DNA hypermethylation as shown by the restoration of TERT transcript levels in cells treated with 5'-azacytidine, an inhibitor of DNA methylation. This was confirmed in infected mice, by PCR-methylation assay of the TERT gene promoter. Our data unraveled a novel way for H. pylori to promote genome instabilities through the inhibition of TERT levels and telomerase activity. This mechanism could play an important role in the early steps of gastric carcinogenesis.
Project description:Telomerase reverse transcriptase (TERT/hTERT) serves as the pivotal catalytic subunit of telomerase, a crucial enzyme responsible for telomere maintenance and human genome stability. The high activation of hTERT, observed in over 90% of tumors, plays a significant role in tumor initiation and progression. An in-depth exploration of hTERT activation mechanisms in cancer holds promise for advancing our understanding of the disease and developing more effective treatment strategies. In breast cancer, the expression of hTERT is regulated by epigenetic, transcriptional, post-translational modification mechanisms and DNA variation. Besides its canonical function in telomere maintenance, hTERT exerts non-canonical roles that contribute to disease progression through telomerase-independent mechanisms. This comprehensive review summarizes the regulatory mechanisms governing hTERT in breast cancer and elucidates the functional implications of its activation. Given the overexpression of hTERT in most breast cancer cells, the detection of hTERT and its associated molecules are potential for enhancing early screening and prognostic evaluation of breast cancer. Although still in its early stages, therapeutic approaches targeting hTERT and its regulatory molecules show promise as viable strategies for breast cancer treatment. These methods are also discussed in this paper. Video Abstract.
Project description:Telomerase reverse transcriptase (TERT) promoter mutations have been recognized as a common genetic event in bladder cancer (BC). Many studies have found the high TERT promoter mutations' prevalence in BC recurrence patients which may make the TERT promoter mutations become a potential prognosis prediction of BC. We performed a systematic search in Embase, PubMed, and Web of Science in January 2021. The aspects of evaluation, methods, validation, and results were used to evaluate the included studies' quality. We reviewed two of the most common mutations in types of TC, C288T and C250T and their relationship with prognosis of BC. Eight studies contained 1382 cases were enrolled in our study. The percentage of TERT promoter mutations in these cases was 62.5%. A statistically significant association was detected between TERT promoter mutation and recurrence (HR: 2.03, 95% CI: 1.53-2.68, p < 0.001). However, TERT promoter mutation was not significant associated with overall survival (HR: 1.077, 95% CI: 0.674-1.718, p = 0.757). No significant heterogeneities were observed (I2 = 47.5%, P = 0.064; I2 = 58.7%, p = 0.120, respectively). Bladder cancer patients with TERT promoter mutations take a higher risk of recurrence. TERT promoter mutations may become a potential prediction factor for bladder cancer recurrence.
Project description:Telomerase activity and telomere elongation are essential conditions for the unlimited proliferation of neoplastic cells. Point mutations in the core promoter region of the telomerase reverse transcriptase (TERT) gene have been found to occur at high frequencies in several tumour types and considered a primary cause of telomerase reactivation in cancer cells. These mutations promote TERT gene expression by multiple mechanisms, including the generation of novel binding sites for nuclear transcription factors, displacement of negative regulators from DNA G-quadruplexes, recruitment of epigenetic activators and disruption of long-range interactions between TERT locus and telomeres. Furthermore, TERT promoter mutations cooperate with TPP1 promoter nucleotide changes to lengthen telomeres and with mutated BRAF and FGFR3 oncoproteins to enhance oncogenic signalling in cancer cells. TERT promoter mutations have been recognized as an early marker of tumour development or a major indicator of poor outcome and reduced patients survival in several cancer types. In this review, we summarize recent findings on the role of TERT promoter mutations, telomerase expression and telomeres elongation in cancer development, their clinical significance and therapeutic opportunities.
Project description: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.
Project description:The Mexican axolotl is one of the few vertebrates that is able to replace its lost body parts during lifespan. Due to its remarkable regenerative abilities, the axolotl emerged as a model organism especially for limb regeneration. Telomeres and the telomerase enzyme are crucial for regeneration and protection against aging processes and degenerating diseases. Despite its relevance for regeneration, the axolotl telomerase and telomere length have not yet been investigated. Therefore, in the present paper, we reveal the sequence of the axolotl telomerase reverse transcriptase gene (Tert) and protein (TERT). Multiple sequence alignment (MSA) showed the known conserved RT- and TERT-specific motifs and residues found in other TERTs. In addition, we establish methods to determine the Tert expression (RT-PCR) and telomerase activity (Q-TRAP) of adult axolotl and blastema tissues. We found that both differentiated forelimb tissue and regenerating blastema tissue express Tert and show telomerase activity. Furthermore, blastema tissue appears to exhibit a higher Tert expression and telomerase activity. The presence of active telomerase in adult somatic cells is a decisive difference to somatic cells of non-regenerating vertebrates, such as humans. These findings indicate that telomere biology may play a key role in the regenerative abilities of cells.
Project description:Telomerase reverse transcriptase (TERT) is pathologically expressed in the vast majority of human cancers, but the epigenetic regulation of its expression is only beginning to be understood. In particular, the active TERT gene in cancer cells has been characterized as having a hypermethylated CpG island, opposite to the general association of DNA methylation with gene repression. Here, we analyzed TERT promoter CpG methylation in 833 human cancer cell lines representing 23 different tissue types and found hypermethylation of the upstream portion of the CpG island and more conserved hypomethylation of a region including the proximal TERT promoter and exon 1. In cell lines with monoallelic expression of TERT, we found allelic methylation of the proximal TERT promoter. This included cell lines with the -124 or -146 activating promoter mutation as well as wild-type TERT cancer lines. In these cell line types, decreased proximal promoter methylation is associated with the active allele. Compared to cells with monoallelic expression of TERT, lines with biallelic expression of TERT had even lower methylation in the proximal TERT promoter. Thus, in cell lines from cancers of many different tissues, the TERT proximal promoter has canonical DNA methylation, with low methylation correlating with increased TERT expression.