Association of ADC of hyperintense lesions on FLAIR images with TERT promoter mutation status in glioblastoma IDH wild type.

Background: Although mutations in telomerase reverse transcriptase (TERT) promoter (TERTp) are the most common alterations in glioblastoma (GBM), predicting TERTp mutation status by preoperative imaging is difficult. We determined whether tumour-surrounding hyperintense lesions on fluid-attenuated inversion recovery (FLAIR) were superior to those of contrast-enhanced lesions (CELs) in assessing TERTp mutation status using magnetic resonance imaging (MRI). Methods: This retrospective study included 114 consecutive patients with primary isocitrate dehydrogenase (IDH)-wild-type GBM. The apparent diffusion coefficient (ADC) and volume of CELs and FLAIR hyperintense lesions (FHLs) were determined, and the correlation between MRI features and TERTp mutation status was analyzed. In a subset of cases, FHLs were histopathologically analyzed to determine the correlation between tumor cell density and ADC. Results: TERTp mutations were present in 77 (67.5%) patients. The minimum ADC of FHLs was significantly lower in the TERTp-mutant group than in the TERTp-wild-type group (mean, 958.9 × 10-3 and 1092.1 × 10-3 mm2/s, respectively, P < 0.01). However, other MRI features, such as CEL and FHL volumes, minimum ADC of CELs, and FHL/CEL ratio, were not significantly different between the two groups. Histopathologic analysis indicated high tumor cell density in FHLs with low ADC. Conclusion: The ADC of FHLs was significantly lower in IDH-wild-type GBM with TERTp mutations, suggesting that determining the ADC of FHLs on preoperative MRI might be helpful in predicting TERTp mutation status and surgical planning.

Novel Immortalized Human Multipotent Mesenchymal Stromal Cell Line for Studying Hormonal Signaling.

Multipotent mesenchymal stromal cells (MSCs) integrate hormone and neuromediator signaling to coordinate tissue homeostasis, tissue renewal and regeneration. To facilitate the investigation of MSC biology, stable immortalized cell lines are created (e.g., commercially available ASC52telo). However, the ASC52telo cell line has an impaired adipogenic ability and a depressed response to hormones, including 5-HT, GABA, glutamate, noradrenaline, PTH and insulin compared to primary cells. This markedly reduces the potential of the ASC52telo cell line in studying the mechanisms of hormonal control of MSC's physiology. Here, we have established a novel immortalized culture of adipose tissue-derived MSCs via forced telomerase expression after lentiviral transduction. These immortalized cell cultures demonstrate high proliferative potential (up to 40 passages), delayed senescence, as well as preserved primary culture-like functional activity (sensitivity to hormones, ability to hormonal sensitization and differentiation) and immunophenotype up to 17-26 passages. Meanwhile, primary adipose tissue-derived MSCs usually irreversibly lose their properties by 8-10 passages. Observed characteristics of reported immortalized human MSC cultures make them a feasible model for studying molecular mechanisms, which regulate the functional activities of these cells, especially when primary cultures or commercially available cell lines are not appropriate.

The role of telomerase in hair growth and relevant disorders: A review.

BACKGROUND: Hair diseases may present with hair loss, hirsutism, hair melanin abnormalities and other manifestations. Hair follicles are known as mini-organs that undergo periodic remodeling, and their constant regeneration in vivo reflects interesting anti-aging functions. Telomerase prevents cellular senescence by maintaining telomere length, but its excessive proliferation in cancer cells may also induce cancer. However, the effects of telomerase in hair growth have rarely been reported. METHODS: In this study, we reviewed the role of telomerase in hair growth and the effects of hair disorders through literature search and analysis. RESULTS: There is growing evidence that telomerase plays an important role in maintaining hair follicle function and proliferation. Changes in telomerase levels in hair follicles have also been found in a variety of hair disorders. CONCLUSION: Telomerase plays a positive role in hair growth and is expected to become a new target for the treatment of alopecia or other hair diseases in the future.

Prognostic value and immune landscapes of TERT promoter methylation in triple negative breast cancer.

Background: Treatment options for patients with triple-negative breast cancer (TNBC) remain limited to mainstay therapies owing to a lack of efficacious therapeutic targets. Accordingly, there is an urgent need to discover and identify novel molecular targets for the treatment and diagnosis of this disease. In this study, we analyzed the correlation of telomerase reverse transcriptase (TERT) methylation status with TERT expression, prognosis, and immune infiltration in TNBC and identified the role of TERT methylation in the regulation TNBC prognosis and immunotherapy. Methods: Data relating to the transcriptome, clinicopathological characteristics and methylation of TNBC patients were obtained from The Cancer Genome Atlas (TCGA) database. TERT expression levels and differential methylation sites (DMSs) were detected. The correlations between TERT expression and DMSs were calculated. Kaplan-Meier curves was plotted to analyze the relationship between the survival of TNBC patients and the DMSs. The correlations of DMSs and TERT expression with several immunological characteristics of immune microenvironment (immune cell infiltration, immunomodulators, immune-related biological pathways, and immune checkpoints) were assessed. The results were validated using 40 TNBC patients from Sun Yat-sen University Cancer Center (SYSUCC). Results: Six DMSs were identified. Among them, four sites (cg11625005, cg07380026, cg17166338, and cg26006951) were within the TERT promoter, in which two sites (cg07380026 and cg26006951) were significantly related to the prognosis of patients with TNBC. Further validation using 40 TNBC samples from SYSUCC showed that the high methylation of the cg26006951 CpG site was associated with poor survival prognosis (P=0.0022). TERT expression was significantly correlated with pathological N stage and clinical stage, and cg07380026 were significantly associated with pathological T and N stages in the TCGA cohort. Moreover, the methylation site cg26006951, cg07380026 and TERT expression were significantly correlated with immune cell infiltration, common immunomodulators, and the level of the immune checkpoint receptor lymphocyte activation gene 3 (LAG-3) in TNBC patients. Conclusion: TERT promotertypermethylation plays an important role in TERT expression regulation and tumor microenvironment in TNBC. It is associated with overall survival and LAG-3 expression. TERT promoter hypermethylation may be a potential molecular biomarker for predicting response to the TERT inhibitors and immune checkpoint inhibitors in TNBC.

TERT promoter mutations in thyroid cancer.

TERT promoter mutations (TERT-p mutations) have been found in many types of cancer and have emerged to play critical roles in tumor progression. The mutations upregulate TERT transcription, and TERT not only elongates telomeres and confers unlimited proliferative capacity on tumor cells, but is also involved in tumor progression and aggressiveness. In differentiated thyroid carcinoma, TERT-p mutations are associated with a number of high-risk clinicopathological aggressiveness and worse prognosis, making it the best molecular marker to predict tumor aggressiveness so far. This review summarizes recent relevant findings regarding TERT-p mutations and their functional/mechanistic aspects.

Differences in clinical outcomes based on molecular markers in glioblastoma patients treated with concurrent tumor-treating fields and chemoradiation: exploratory analysis of the SPARE trial.

BACKGROUND: Glioblastoma (GBM) is the most common primary malignant brain tumor in adults. Despite enormous research efforts, GBM remains a deadly disease. The standard-of-care treatment for patients with newly diagnosed with GBM as per the National Cancer Comprehensive Cancer Network (NCCN) is maximal safe surgical resection followed by concurrent chemoradiation and maintenance temozolomide (TMZ) with adjuvant tumor treating fields (TTF). TTF is a non-pharmacological intervention that delivers low-intensity, intermediate frequency alternating electric fields that arrests cell proliferation by disrupting the mitotic spindle. TTF have been shown in a large clinical trial to improve patient outcomes when added to radiation and chemotherapy. The SPARE trail (Scalp-sparing radiation with concurrent temozolomide and tumor treating fields) evaluated adding TTF concomitantly to radiation and chemotherapy. METHODS: This study is an exploratory analysis of the SPARE trial looking at the prognostic significance of common GBM molecular alterations, namely MGMT, EGFR, TP53, PTEN and telomerase reverse transcriptase (TERT), in this cohort of patients treated with concomitant TTF with radiation and chemotherapy. RESULTS: As expected, MGMT promoter methylation was associated with improved overall survival (OS) and progression-free survival (PFS) in this cohort. In addition, TERT promoter mutation was associated with improved OS and PFS in this cohort as well. CONCLUSIONS: Leveraging the molecular characterization of GBM alongside advancing treatments such as chemoradiation with TTF presents a new opportunity to improve precision oncology and outcomes for GBM patients.

Deciphering the Functions of Telomerase Reverse Transcriptase in Head and Neck Cancer.

Head and neck cancers (HNCs) are among the ten leading malignancies worldwide. Despite significant progress in all therapeutic modalities, predictive biomarkers, and targeted therapies for HNCs are limited and the survival rate is unsatisfactory. The importance of telomere maintenance via telomerase reactivation in carcinogenesis has been demonstrated in recent decades. Several mechanisms could activate telomerase reverse transcriptase (TERT), the most common of which is promoter alternation. Two major hotspot TERT promoter mutations (C228T and C250T) have been reported in different malignancies such as melanoma, genitourinary cancers, CNS tumors, hepatocellular carcinoma, thyroid cancers, sarcomas, and HNCs. The frequencies of TERT promoter mutations vary widely across tumors and is quite high in HNCs (11.9-64.7%). These mutations have been reported to be more enriched in oral cavity SCCs and HPV-negative tumors. The association between TERT promoter mutations and poor survival has also been demonstrated. Till now, several therapeutic strategies targeting telomerase have been developed although only a few drugs have been used in clinical trials. Here, we briefly review and summarize our current understanding and evidence of TERT promoter mutations in HNC patients.

Association of the Telomerase Reverse Transcriptase rs10069690 Polymorphism with the Risk, Age at Onset and Prognosis of Triple Negative Breast Cancer.

Telomerase reverse transcriptase (TERT) plays a key role in the maintenance of telomere DNA length. The rs10069690 single nucleotide variant, located in intron 4 of TERT, was found to be associated with telomere length and the risk of estrogen receptor-negative but not-positive breast cancer. This study aimed at analysis of the association of rs10069690 genotype and TERT expression with the risk, age at onset, prognosis, and clinically and molecularly relevant subtypes of breast cancer. Accordingly, rs10069690 was genotyped in a hospital-based case-control study of 403 female breast cancer patients and 246 female controls of a Central European (Austrian) study population, and the mRNA levels of TERT were quantified in 106 primary breast tumors using qRT-PCR. We found that in triple-negative breast cancer patients, the minor rs10069690 TT genotype tended to be associated with an increased breast cancer risk (OR, 1.87; 95% CI, 0.75-4.71; p = 0.155) and was significantly associated with 11.7 years younger age at breast cancer onset (p = 0.0002), whereas the CC genotype was associated with a poor brain metastasis-free survival (p = 0.009). Overall, our data show that the rs10069690 CC genotype and a high TERT expression tended to be associated with each other and with a poor prognosis. Our findings indicate a key role of rs10069690 in triple-negative breast cancer.

A RUNX1/ETO-SKP2-CDKN1B axis regulates expression of telomerase in t (8;21) acute myeloid leukemia.

The fusion oncoprotein RUNX1/ETO which results from the chromosomal translocation t (8;21) in acute myeloid leukemia (AML) is an essential driver of leukemic maintenance. We have previously shown that RUNX1/ETO knockdown impairs expression of the protein component of telomerase, TERT. However, the underlying molecular mechanism of how RUNX1/ETO controls TERT expression has not been fully elucidated. Here we show that RUNX1/ETO binds to an intergenic region 18 kb upstream of the TERT transcriptional start site and to a site located in intron 6 of TERT. Loss of RUNX1/ETO binding precedes inhibition of TERT expression. Repression of TERT expression is also dependent on the destabilization of the E3 ubiquitin ligase SKP2 and the resultant accumulation of the cell cycle inhibitor CDKN1B, that are both associated with RUNX1/ETO knockdown. Increased CDKN1B protein levels ultimately diminished TERT transcription with E2F1/Rb involvement. Collectively, our results show that RUNX1/ETO controls TERT expression directly by binding to its locus and indirectly via a SKP2-CDKN1B-E2F1/Rb axis.

Biological and clinical perspectives of TERT promoter mutation detection on bladder cancer diagnosis and management.

The telomerase reverse transcriptase (TERT) promoter mutations are associated with increased TERT mRNA and TERT protein levels, telomerase activity, and shorter but stable telomere length. TERT promoter mutation is the most common mutation that occurs in approximately 60-80% of patients with bladder cancer. The TERT promoter mutations occur in a wide spectrum of urothelial lesions, including benign urothelial proliferation and tumor-like conditions, benign urothelial tumors, premalignant and putative precursor lesions, urothelial carcinoma and its variants, and nonurothelial malignancies. The prevalence and incidence of TERT promoter mutations in a total of 7259 cases from the urinary tract were systematically reviewed. Different platforms of TERT promoter mutation detection were presented. In this review, we also discussed the significance and clinical implications of TERT promoter mutation detection in urothelial tumorigenesis, surveillance and early detection, diagnosis, differential diagnosis, prognosis, prediction of treatment responses, and clinical outcome. Identification of TERT promoter mutations from urine or plasma cell-free DNA (liquid biopsy) will facilitate bladder cancer screening program and optimal clinical management. A better understanding of TERT promoter mutation and its pathway would open new therapeutic avenues for patients with bladder cancer.

Prognostic and Clinicopathological Significance of Telomerase Reverse Transcriptase Upregulation in Oral Cancer: A Systematic Review and Meta-Analysis.

The aim of this systematic review and meta-analysis was to evaluate the current evidence on the prognostic and clinicopathological significance value of telomerase reverse transcriptase (TERT) upregulation in patients with oral squamous cell carcinoma (OSCC). PubMed, Embase, Web of Science, and Scopus were searched for studies published before April 2022, not restricted by date or publication language. The methodological quality of primary-level studies was critically assessed using the Quality in Prognosis Studies (QUIPS) tool. We carried out meta-analyses, explored heterogeneity and its sources, and performed subgroup, meta-regression, sensitivity, and small-study effects analyses. Twenty-one studies (1698 patients) met inclusion criteria. TERT protein overexpression was significantly associated with worse overall survival (hazard ratio [HR] = 3.01, 95% CI = 1.70−5.35, p < 0.001), disease-free survival (HR = 4.03, 95% CI = 1.80−9.05, p = 0.001), and higher histological grade OSCC (odds ratio [OR] = 3.20, 95% CI = 1.83−5.62, p < 0.001). These large effect sizes were consistently obtained by homogeneous subgroups (p > 0.10, I2 = 0.0, respectively), which reflects a high quality of evidence. On the other hand, TERT gene mutations obtained constantly nonsignificant null effect sizes for all outcomes investigated, evidencing no prognostic or clinicopathological value. In conclusion, our findings indicate that TERT upregulation is a prognostic indicator of poor survival in oral cancer. Our findings support the immunohistochemical assessment of TERT overexpression, which could probably be incorporated into the prognostic evaluation of OSCC.

Telomerase positive CTCs with PSMA high expression associated with prostate cancer metastasis.

Background: Whether circulating tumor cells (CTCs) with prostate-specific membrane antigen (PSMA) high expression was related to the metastatic progress in prostate cancer (PCa) remains explored. This study aimed to provide evidence to elucidate this relationship via the telomerase reverse transcriptase (TERT)-based CTC detection method. Methods: A total of 71 patients were enrolled and divided into the local PCa group (n=44) and metastatic PCa group (n=27). TERT-based CTC detection (TBCD) was used to detect CTCs. CTCs single-cell sequencing data were analyzed using gene ontology (GO) functional classification and enrichment. Results: The mean 'TERT+ CTCs' number was 6.11±9.63 in the metastatic group and 4.09±3.41 in the local group. GO enrichment analysis for 77 prostate CTCs single-cell sequencing confirmed that proliferation-related terms were enriched in the PSMA-high expression group, and 27 metastasis-related gene panels also had high expression in this group. Then, PSMA antibody was applied to mark the 'TERT+ CTCs'. The proportion of patients with 'TERT+ PSMA+ CTCs' was positively associated with the Gleason score. Furthermore, the proportion of 'TERT+ PSMA+ CTCs' patients was 48.15% in the metastatic group, significantly higher than 22.72% in the local group. Conclusions: This study suggested that TERT positive CTCs with high PSMA expression were associated with the PCa metastatic progress.

Relationship between Telomere Length, TERT Genetic Variability and TERT, TP53, SP1, MYC Gene Co-Expression in the Clinicopathological Profile of Breast Cancer.

The molecular mechanisms of telomerase reverse transcriptase (TERT) upregulation in breast cancer (BC) are complex. We compared genetic variability within TERT and telomere length with the clinical data of patients with BC. Additionally, we assessed the expression of the TERT, MYC, TP53 and SP1 genes in BC patients and in BC organoids (3D cell cultures obtained from breast cancer tissues). We observed the same correlation in the blood of BC patients and in BC organoids between the expression of TERT and TP53. Only in BC patients was a correlation found between the expression of the TERT and MYC genes and between TP53 and MYC. We found associations between TERT genotypes (rs2735940 and rs10069690) and TP53 expression and telomere length. BC patients with the TT genotype rs2735940 have a shorter telomere length, but patients with A allele rs10069690 have a longer telomere length. BC patients with a short allele VNTR-MNS16A showed higher expression of the SP1 and had a longer telomere. Our results bring new insight into the regulation of TERT, MYC, TP53 and SP1 gene expression related to TERT genetic variability and telomere length. Our study also showed for the first time a similar relationship in the expression of the above genes in BC patients and in BC organoids. These findings suggest that TERT genetic variability, expression and telomere length might be useful biomarkers for BC, but their prognostic value may vary depending on the clinical parameters of BC patients and tumor aggressiveness.

An Identification and Characterization of the Axolotl (Ambystoma mexicanum, Amex) Telomerase Reverse Transcriptase (Amex TERT).

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.

The S-adenosylmethionine analog sinefungin inhibits the trimethylguanosine synthase TGS1 to promote telomerase activity and telomere lengthening.

Mutations in many genes that control the expression, the function, or the stability of telomerase cause telomere biology disorders (TBDs), such as dyskeratosis congenita, pulmonary fibrosis, and aplastic anemia. Mutations in a subset of the genes associated with TBDs cause reductions of the telomerase RNA moiety hTR, thus limiting telomerase activity. We have recently found that loss of the trimethylguanosine synthase TGS1 increases both hTR abundance and telomerase activity and leads to telomere elongation. Here, we show that treatment with the S-adenosylmethionine analog sinefungin inhibits TGS1 activity, increases the hTR levels, and promotes telomere lengthening in different cell types. Our results hold promise for restoring telomere length in stem and progenitor cells from TBD patients with reduced hTR levels.

Bilateral Thalamic Glioma: A Case Report.

Bilateral thalamic primary gliomas are an exceedingly rare entity. Symptomology heralding a workup and diagnosis of bithalamic gliomas is diverse and varies between the pediatric and adult populations. Herein, we present a case of a 63-year-old female patient who presented with progressive gait imbalance and fatigue, prompting an outpatient brain MRI, remarkable for marked expansion of the bilateral thalami secondary to non-enhancing, T2-weighted-fluid-attenuated inversion recovery (T2-FLAIR) bright bithalamic lesions. The patient underwent a right frontal frameless stereotactic biopsy of the right thalamic lesion, with immuno-histology indicating a high-grade anaplastic astrocytoma with molecular features of glioblastoma (GBM). The patient's functional status declined precipitously in the month following her diagnostic biopsy, precluding any therapy, and the patient ultimately pursued home hospice care without further treatment. This case details the clinical management of a very rare tumor, supplementing the available literature on the progression and treatment of this rare disease.

Establishment of an Efficient Immortalization Strategy Using HMEJ-Based bTERT Insertion for Bovine Cells.

Immortalized cell lines have been used in a wide range of applications in research on immune disorders and cellular metabolic regulation due to the stability and uniformity of their cellular characteristics. At present, the investigation into molecular functions and signaling pathways within bovine cells remains largely limited by the lack of immortalized model cells. Current methods for immortalizing bovine cells are mainly restricted to the ectopic expression of human telomerase reverse transcriptase (hTERT) through transient transfection or virus-mediated delivery, which have defects in efficiency and reliability. In this study, we identified bovine TERT (bTERT) as a novel potent biofactor for immortalizing bovine cells with great advantages over hTERT, and established an efficient and easily manipulated strategy for the immortalization of bovine primary cells. Through the homology-mediated end-joining-based insertion of bTERT at the ROSA26 locus, we successfully generated immortalized bovine fetal fibroblast cell lines with stable characteristics. The observed limitation of this strategy in immortalizing bovine bone marrow-derived macrophages was attributed to the post-translational modification of bTERT, causing inhibited nuclear localization and depressed activity of bTERT in this terminally differentiated cell. In summary, we constructed an innovative method to achieve the high-quality immortalization of bovine primary cells, thereby expanding the prospects for the future application of immortalized bovine model cell lines.

Prognostic Association of TERC, TERT Gene Polymorphism, and Leukocyte Telomere Length in Acute Heart Failure: A Prospective Study.

Background: Telomere length and telomerase are associated in development of cardiovascular diseases. Study aims to investigate the associations of TERC and TERT gene polymorphism and leukocyte telomere length (LTL) in the prognosis of acute heart failure (AHF). Methods: Total 322 patients with AHF were enrolled and divided into death and survival group according to all-cause mortality within 18 months. Seven single nucleotide polymorphisms (SNPs) of TERC and TERT were selected. Baseline characteristics, genotype distribution and polymorphic allele frequency, and genetic model were initially analyzed. Genotypes and the LTL were determined for further analysis. Results: Compared to carrying homozygous wild genotype, the risk of death in patients with mutated alleles of four SNPs- rs12696304(G>C), rs10936599(T>C), rs1317082(G>A), and rs10936601(T>C) of TERC were significantly higher. The dominant models of above were independently associated with mortality. In recessive models, rs10936599 and rs1317082 of TERC, rs7726159 of TERT were independently associated with long-term mortality. Further analysis showed, in haplotype consisting with TERC - rs12696304, rs10936599, rs1317082, and rs10936601, mutant alleles CCAC and wild alleles GTGT were significant difference between groups (P<0.05). CCAC is a risk factor and GTGT is a protective factor for AHF patients. Relative LTL decreased over age, but showed no difference between groups and genotypes. Conclusions: The SNPs of TERC and TERT are associated with the prognosis of AHF, and are the independent risk factors for predicting 18-month mortality in AHF.

Poly(U) binding splicing factor 60 promotes renal cell carcinoma growth by transcriptionally upregulating telomerase reverse transcriptase.

Background: Abnormal transcriptional upregulation of telomerase reverse transcriptase (TERT) plays a dominant role in telomerase activation in various cancers. TERT promoter mutations (TPMs) have been identified as a key mechanism in TERT upregulation. However, the mechanism of TERT upregulation in cancers with low frequency of TPMs are not fully elucidated so far. Methods: The expression of PUF60 and TERT was detected by real-time PCR, western blot and immunohistochemistry. TERT promoter binding proteins were identified by streptavidin-agarose pulldown assay and mass spectrum (MS) analysis. The role of PUF60/TERT in renal cancer was evaluated on cell growth in vitro and in vivo. Results: In this study, we identify the regulation mechanism of TERT in renal cell carcinoma (RCC) cells which have rare TPMs but exert significant upregulation of TERT. We found that TERT was highly expressed in RCC tumor tissues, and elevated TERT expression was associated with poor prognosis for patients. We also detected the relatively rare TPM status in both RCC tumor tissues and RCC cell lines. Mechanistically, PUF60, a RNA binding protein, was identified as a novel TERT regulator which bound to the TERT and transcriptionally upregulated TERT expression in RCC cells. The in vitro and in vivo experiments also demonstrated that PUF60 could promote RCC cell growth through activation of TERT expression in a TPM status independent way. Furthermore, we showed that there was a strong correlation of the expression of PUF60 and TERT in RCC tumor tissues and RCC cell lines, and the patients with high expression of PUF60 and TERT had significantly shorter survival. Conclusions: Collectively, these results indicated that PUF60 transcriptionally upregulated TERT expression to promote RCC growth and progression in a TPM status independent way, suggesting that the PUF60/TERT signaling pathway may serve as potential prognostic biomarkers and therapeutic targets for RCC.

Composition and Function of Telomerase-A Polymerase Associated with the Origin of Eukaryotes.

The canonical DNA polymerases involved in the replication of the genome are unable to fully replicate the physical ends of linear chromosomes, called telomeres. Chromosomal termini thus become shortened in each cell cycle. The maintenance of telomeres requires telomerase-a specific RNA-dependent DNA polymerase enzyme complex that carries its own RNA template and adds telomeric repeats to the ends of chromosomes using a reverse transcription mechanism. Both core subunits of telomerase-its catalytic telomerase reverse transcriptase (TERT) subunit and telomerase RNA (TR) component-were identified in quick succession in Tetrahymena more than 30 years ago. Since then, both telomerase subunits have been described in various organisms including yeasts, mammals, birds, reptiles and fish. Despite the fact that telomerase activity in plants was described 25 years ago and the TERT subunit four years later, a genuine plant TR has only recently been identified by our group. In this review, we focus on the structure, composition and function of telomerases. In addition, we discuss the origin and phylogenetic divergence of this unique RNA-dependent DNA polymerase as a witness of early eukaryotic evolution. Specifically, we discuss the latest information regarding the recently discovered TR component in plants, its conservation and its structural features.