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Journal articles on the topic 'HTERC'

Author: Grafiati

Published: 4 June 2021

Last updated: 1 February 2022

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1

Xin, Zhong-Tao, Adam D. Beauchamp, Rodrigo T. Calado, Jennifer W. Bradford, Joshua A. Regal, Aarthi Shenoy, Yuying Liang, Peter M. Lansdorp, Neal S. Young, and Hinh Ly. "Functional characterization of natural telomerase mutations found in patients with hematologic disorders." Blood 109, no. 2 (September 21, 2006): 524–32. http://dx.doi.org/10.1182/blood-2006-07-035089.

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Abstract Human telomerase hTERC RNA serves as a template for the catalytic hTERT protein to synthesize telomere repeats at chromosome ends. We have recently shown that some patients with bone marrow failure syndromes are heterozygous carriers for hTERC or hTERT mutations. These sequence variations usually lead to a compromised telomerase function by haploinsufficiency. Here, we provide functional characterization of an additional 8 distinct hTERT sequence variants and 5 hTERC variants that have recently been identified in patients with dyskeratosis congenita (DC) or aplastic anemia (AA). Among the mutations, 2 are novel telomerase variants that were identified in our cohort of patients. Whereas most of the sequence variants modulate telomerase function by haploinsufficiency, 2 hTERC variants with sequence changes located within the template region appear to act in a dominant-negative fashion. Inherited telomerase gene mutations, therefore, operate by various mechanisms to shorten telomere lengths, leading to limited marrow stem cell reserve and renewal capacity in patients with hematologic disorders.

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2

Yang, Jing-Hua, Ming-Zhe Wu, Xu-Bo Wang, Shiyu Wang, Xue-Shan Qiu, En-Hua Wang, and Guang-Ping Wu. "HPV16 E6/E7 upregulate hTERC mRNA and gene amplification levels by relieving the effect of LKB1 on Sp1 phosphorylation in lung cancer cells." Therapeutic Advances in Medical Oncology 12 (January 2020): 175883592091756. http://dx.doi.org/10.1177/1758835920917562.

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Background: There is an immediate need for research on the mechanism underlying telomerase activation and overexpression. Materials & Methods: A total of 174 patients with lung cancer ( n = 106) and benign lung disease ( n = 68) were recruited for the current study. The mRNA expression levels of E6, E7, LKB1, Sp1, and hTERC in brushing cells were detected by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR), and hTERC amplification was also detected by fluorescence in situ hybridization (FISH). To investigate the potential mechanism, bidirectional genetic manipulation was performed in well-established lung cancer cell lines. Results: Our results indicated that the mRNA expression levels of E6, E7, Sp1, and hTERC and the amplification level of hTERC were significantly increased in the malignant group compared with those of the benign group ( p < 0.01). Conversely, the mRNA expression level of LKB1 was significantly decreased in the malignant group ( p < 0.01). The correlation between E6, E7, Sp1, and hTERC expression was positive but was negative with LKB1 ( p < 0.01). Our results also showed that HPV16 E6/E7 downregulated the expression of LKB1 at both the protein and mRNA levels. The loss of LKB1 upregulated Sp1 expression, and also promoted Sp1 activity. Sp1 further upregulated hTERC at the mRNA and gene amplification levels. Thus, we proposed a HPV–LKB1–Sp1–hTERC axis of E6/E7 upregulation of hTERC expression. Conclusion: We demonstrated for the first time that E6 and E7 promoted hTERC mRNA expression and the amplification of hTERC by relieving the effect of LKB1 on the phosphorylation of Sp1. Sp1 further activated hTERC by directly binding to the promoter regions of hTERC.

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Garrels, W., W. Kues, U. Baulain, and H. Niemann. "161 MODULATION OF TELOMERASE ACTIVITY IN BOVINE EMBRYOS USING CYTOPLASMATIC PLASMID INJECTION." Reproduction, Fertility and Development 22, no. 1 (2010): 239. http://dx.doi.org/10.1071/rdv22n1ab161.

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Telomeres are repetitive, noncoding sequences at the ends of linear chromosomes that shorten with each cell division. They play an important role in aging and affect the regenerative capacity of cells. The holoenzyme telomerase rebuilds telomeres and is composed of 2 components, i.e. the catalytic protein component telomerase reverse transcriptase (TERT) and the telomerase RNA component (TERC). In mammals, telomerase is active during embryogenesis, in germ cells and a subset of stem and progenitor cells. In the present study, we set out to express the TERC component alone and then in combination with TERT, the human telomerase complex, in bovine embryos. The human telomerase components are highly homologous to bovine telomerase genes. Here, 3 different expression constructs encoding hTERC, hTERT, and a green fluorescent protein (GFP) reporter were co-injected into bovine zygotes cytoplasm, and three groups of 528, 1865, and 110 zygotes were constituted; hTERC/GFP (Group 1), hTERT/hTERC/GFP (Group 2), and GFP alone (Group 3), respectively. GFP fluorescence was used to identify successfully injected embryos. This method has recently been established in our laboratory. Injected and control embryos were cultured for 7 days to the blastocyst stage in vitro and the impact on early embryonic development and the physiological consequences of an ectopic overexpression of telomerase in early bovine embryos were assayed. We obtained 45 blastocysts with green fluorescence in the first, 192 in the second, and 28 in the third group. Embryos with GFP fluorescence were frozen for subsequent PCR analysis and telomerase activity measurement. Some blastocyts were analyzed using quantitative fluoresence in situ hybridization to monitor telomere length. Control groups were analyzed for the endogenous levels of TERC and TERT. Results indicate that endogenous TERC and TERT are up-regulated in morulae and blastocyts. In this study, we show that human TERC and TERT can be expressed in blastocysts by cytoplasmic plasmid injection in bovine zygotes. Statistical analyses were performed using the JMP 7.0.1 for Windows software (SAS Institute Inc., Cary, NC, USA). The Tukey-Kramer test was applied to compare the group means. The expression of hTERC alone resulted in a significant extension of telomere length of 280 telomere fluorescence units. Expression of both components also resulted in a significant extension of telomere length. In conclusion, TERC component alone is sufficient to elongate telomere length. The activity measurement showed that telomerase activity in the hTERT and hTERC injected group is 1.77 times higher than in the control group. Findings from this study will allow a comprehensive analysis of the functions of TERT and TERC in early embryogenesis. The ectopic expression of telomerase components in bovine embryos could pave new avenues for generating stem cells and for the development of novel regenerative therapies. Funded by DFG.

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4

Alnafakh, Rafah, Fiona Choi, Alice Bradfield, Meera Adishesh, Gabriele Saretzki, and Dharani K. Hapangama. "Endometriosis Is Associated with a Significant Increase in hTERC and Altered Telomere/Telomerase Associated Genes in the Eutopic Endometrium, an Ex-Vivo and In Silico Study." Biomedicines 8, no. 12 (December 9, 2020): 588. http://dx.doi.org/10.3390/biomedicines8120588.

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Telomeres protect chromosomal ends and they are maintained by the specialised enzyme, telomerase. Endometriosis is a common gynaecological disease and high telomerase activity and higher hTERT levels associated with longer endometrial telomere lengths are characteristics of eutopic secretory endometrial aberrations of women with endometriosis. Our ex-vivo study examined the levels of hTERC and DKC1 RNA and dyskerin protein levels in the endometrium from healthy women and those with endometriosis (n = 117). The in silico study examined endometriosis-specific telomere- and telomerase-associated gene (TTAG) transcriptional aberrations of secretory phase eutopic endometrium utilising publicly available microarray datasets. Eutopic secretory endometrial hTERC levels were significantly increased in women with endometriosis compared to healthy endometrium, yet dyskerin mRNA and protein levels were unperturbed. Our in silico study identified 10 TTAGs (CDKN2A, PML, ZNHIT2, UBE3A, MCCC2, HSPC159, FGFR2, PIK3C2A, RALGAPA1, and HNRNPA2B1) to be altered in mid-secretory endometrium of women with endometriosis. High levels of hTERC and the identified other TTAGs might be part of the established alteration in the eutopic endometrial telomerase biology in women with endometriosis in the secretory phase of the endometrium and our data informs future research to unravel the fundamental involvement of telomerase in the pathogenesis of endometriosis.

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5

Xu, Chenzhong, Nan Xie, Yuanyuan Su, Zhaomeng Sun, Yao Liang, Na Zhang, Doudou Liu, et al. "HnRNP F/H associate with hTERC and telomerase holoenzyme to modulate telomerase function and promote cell proliferation." Cell Death & Differentiation 27, no. 6 (December 20, 2019): 1998–2013. http://dx.doi.org/10.1038/s41418-019-0483-6.

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AbstractHuman telomerase RNA component hTERC comprises multiple motifs that contribute to hTERC biogenesis, holoenzyme activity, and enzyme recruitment to telomeres. hTERC contains several guanine tracts (G-tracts) at its 5′-end, but its associated proteins and potential roles in telomerase function are still poorly understood. The heterogeneous nuclear ribonucleoproteins F, H1, and H2 (hnRNP F/H) are splicing factors that preferentially bind to poly(G)-rich sequences RNA. Here, we demonstrate that hnRNP F/H associate with both hTERC and telomerase holoenzyme to regulate telomerase activity. We reveal hnRNP F/H bind to the 5′-end region of hTERC in vitro and in vivo, and identify the first three G-tracts of hTERC and qRRM1 domain of hnRNP F/H are required for their interaction. Furthermore, hnRNP F/H also directly interact with telomerase holoenzyme. Functionally, we show that hnRNP F/H plays important roles in modulating telomerase activity and telomere length. Moreover, hnRNP F/H deletion greatly impair cancer and stem cell proliferation, and induce stem cell senescence, while hnRNP F/H overexpression delay stem cell senescence. Collectively, our findings unveil a novel role of hnRNP F/H as the binding partners of hTERC and telomerase holoenzyme to regulate telomerase function.

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6

Eckburg, Adam, Joshua Dein, Joseph Berei, Zachary Schrank, and Neelu Puri. "Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy." Cancers 12, no. 9 (August 19, 2020): 2337. http://dx.doi.org/10.3390/cancers12092337.

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Telomerase provides cancer cells with replicative immortality, and its overexpression serves as a near-universal marker of cancer. Anti-cancer therapeutics targeting telomerase have garnered interest as possible alternatives to chemotherapy and radiotherapy. Oligonucleotide-based therapies that inhibit telomerase through direct or indirect modulation of its subunits, human telomerase reverse transcriptase (hTERT) and human telomerase RNA gene (hTERC), are a unique and diverse subclass of telomerase inhibitors which hold clinical promise. MicroRNAs that play a role in the upregulation or downregulation of hTERT and respective progression or attenuation of cancer development have been effectively targeted to reduce telomerase activity in various cancer types. Tumor suppressor miRNAs, such as miRNA-512-5p, miRNA-138, and miRNA-128, and oncogenic miRNAs, such as miRNA-19b, miRNA-346, and miRNA-21, have displayed preclinical promise as potential hTERT-based therapeutic targets. Antisense oligonucleotides like GRN163L and T-oligos have also been shown to uniquely target the telomerase subunits and have become popular in the design of novel cancer therapies. Finally, studies suggest that G-quadruplex stabilizers, such as Telomestatin, preserve telomeric oligonucleotide architecture, thus inhibiting hTERC binding to the telomere. This review aims to provide an adept understanding of the conceptual foundation and current state of therapeutics utilizing oligonucleotides to target the telomerase subunits, including the advantages and drawbacks of each of these approaches.

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7

Ly, Hinh, Rodrigo T. Calado, Paulette Allard, Gabriela M. Baerlocher, Peter M. Lansdorp, Neal S. Young, and Tristram G. Parslow. "Functional characterization of telomerase RNA variants found in patients with hematologic disorders." Blood 105, no. 6 (March 15, 2005): 2332–39. http://dx.doi.org/10.1182/blood-2004-09-3659.

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AbstractHuman telomerase uses a specific cellular RNA, called hTERC, as the template to synthesize telomere repeats at chromosome ends. Approximately 10% to 15% of patients with aplastic anemia or other bone marrow failure syndromes are carriers of hTERC sequence variants whose functional significance, in most cases, is unknown. We screened 10 reported and 2 newly discovered hTERC variants from such patients and found that 10 of these negatively affected telomerase enzymatic function when they were used to reconstitute telomerase enzymatic function in human cells. Most functional deficits were due to perturbations of hTERC secondary structure and correlated well with the degrees of telomere shortening and reduced telomerase activity observed in peripheral blood lymphocytes of the representative patients. We also found no evidence of dominant-negative activity in any of the mutants. Therefore, loss of telomerase activity and of telomere maintenance resulting from inherited hTERC mutations may limit marrow stem cell renewal and predispose some patients to bone marrow failure.

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8

Carroll, Kathryn A., Rodrigo Calado, Neal S. Young, Shamika Danzy, and Hinh Ly. "Identification and Functional Characterization of Novel Telomerase Variant Alleles in Patients with Bone-Marrow Failure Syndromes." Blood 112, no. 11 (November 16, 2008): 4113. http://dx.doi.org/10.1182/blood.v112.11.4113.4113.

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Abstract As multiple studies have shown a link between mutations in telomerase components and the disease pathogenesis of bone-marrow failure syndromes (BMFS), we screened blood or marrow cells from patients with various forms of blood disorders for novel pathogenic mutations in the telomerase hTERC and hTERT genes. We identified several heterozygous mutations in these genes, which were observed only in patient samples and not in controls. As these mutations are predicted to affect proper telomerase function, we introduced these and other mutations identified previously in patients with other forms of blood disorders into telomerase-negative cells in order to reconstitute telomerase enzymatic activity and to assess the effect of the individual mutations on modulating a wild-type telomerase function. All disease-associated mutations disrupted telomerase function to various degrees and most modulated a wildtype telomerase enzymatic function by haploinsufficiency based on results obtained from the telomeric repeat amplification protocol (TRAP). We also tested several previously reported natural sequence changes in the promoter region of the hTERC gene for their effect on gene expression and telomerase function via luciferase-reporter assay, TRAP, and Northern blot. The results obtained from these studies appear to contradict those that have recently been reported for some of the naturally occurring hTERC-promoter associated mutations. This study, therefore, offers new insights into the mechanism of natural telomerase mutations in regulating telomere lengths and marrow stem cell renewal capacity in patients with hematological disorders.

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9

Zheng, Xiuhui, Peihe Liang, Yingru Zheng, Ping Yi, Qiang Liu, Jian Han, Yinhu Huang, Yuanguo Zhou, Jianxin Guo, and Li Li. "ATL." International Journal of Gynecologic Cancer 23, no. 5 (June 2013): 785–90. http://dx.doi.org/10.1097/igc.0b013e31828f39a0.

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ObjectiveTo investigate the clinical significance of abnormal human telomerase RNA gene component (hTERC) gene amplification tested by fluorescence in situ hybridization in cervical lesions.MethodsIn 373 patients with cytologic abnormalities, high-risk human papilomavirus (HR-HPV) was detected by the hybrid capture II method, and abnormal amplification of the hTERC gene in exfoliated cells was detected by fluorescence in situ hybridization.ResultsCell smear findings suggested atypical squamous cells in 148 patients, low-grade squamous intraepithelial lesion in 62 patients, and high-grade squamous intraepithelial lesion in 107 patients, squamous cell carcinoma in 56 patients, and cervical biopsy-revealed inflammation in 89 patients, cervical intraepithelial neoplasia (CIN) I in 36 patients, CIN II in 43 patients, CIN III in 129 patients, and infiltrating carcinoma in 76 patients. In the inflammation, CIN I, CIN II, CIN III, and infiltrating carcinoma groups, the infection rates of HR-HPV were 29.21%, 52.78%, 74.42%, 92.25%, and 93.42% (P < 0.01), respectively; the positive rates of hTERC gene amplification were 0.00%, 13.89%, 41.86%, 78.29%, and 89.47% (P < 0.01), respectively. With respect to advanced cervical lesions (≥CIN II), cytology (≥ low-grade squamous intraepithelial lesion), HR-HPV testing, and hTERC testing differed insignificantly in the negative predictive value (P > 0.05), but they differed significantly in the sensitivity, specificity, and positive predictive value (P < 0.01). Among the 3 methods, hTERC testing showed the highest specificity and positive predictive value, and HR-HPV testing showed the highest sensitivity. In 41 patients with untreated CIN I and CIN II, the sensitivity of detection of hTERC gene amplification to predict lesion progression was 88.89%, and the specificity was 93.75%.ConclusionDetection of abnormal amplification of the hTERC gene can assist in screening cervical lesions and identifying CIN I/II patients with a high progression risk.

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Zappacosta, Roberta, Manuel Maria Ianieri, Danilo Buca, Elena Repetti, Alessandra Ricciardulli, and Marco Liberati. "Clinical Role of the Detection of Human Telomerase RNA Component Gene Amplification by Fluorescence in situ Hybridization on Liquid-Based Cervical Samples: Comparison with Human Papillomavirus-DNA Testing and Histopathology." Acta Cytologica 59, no. 4 (2015): 345–54. http://dx.doi.org/10.1159/000438719.

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Objective: This study was designed to evaluate whether the adjunct of human telomerase RNA component (hTERC) fluorescence in situ hybridization (FISH) analysis to cytological diagnosis and human papillomavirus (HPV)-DNA testing may serve as a predictive marker for distinguishing cervical lesions destined to regress from those at high risk of progression towards invasive cancer. Study Design: hTERC FISH analysis was performed on 54 residual liquid-based cytology specimens obtained from women referred to colposcopy for the detection of atypical squamous cells of undetermined significance or worse (ASCUS+) lesions. Histological diagnosis was considered the gold standard and cervical intraepithelial neoplasia of grade 2 or worse (CIN2+) as the worst outcome. Results: Oncogenic HPV-DNA was found in 96.3% of the specimens. Among these, 38.5% revealed a CIN2+ diagnosis. hTERC gene amplification was detected in 37% of the cases; among these, 70% showed up as CIN2+. hTERC FISH analysis significantly improves the specificity and positive predictive value of HPV-DNA testing, thus differentiating patients with a CIN2+ diagnosis from those with a CIN2- diagnosis. Conclusions: Despite the limitation of a small study sample, our findings provide promising data, indicating the possible role of hTERC analysis in the assessment of the risk of developing cervical cancer. This approach would implement the specificity of DNA testing, avoiding overtreatment at the same time. Prospective follow-up studies are needed with the aim of introducing hTERC FISH into decision-making algorithms.

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Benke, Stan, D. S. Houston, Inderjeet Dokal, and Tom Vulliamy. "A Novel hTERC Deletion Manifesting with Features of Dyskeratosis Congenita and Genetic Anticipation." Blood 104, no. 11 (November 16, 2004): 4157. http://dx.doi.org/10.1182/blood.v104.11.4157.4157.

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Abstract The gene encoding the RNA component of human telomerase (hTERC) is mutated in families with the autosomal dominant form of dyskeratosis congenita (DC). The phenomenon of genetic anticipation has recently been reported to accompany this form of DC, with disease severity increasing in offspring of affected individuals. It has been postulated that anticipation in these families relates to the adverse impact of hTERC mutations on inherited telomere length, with progressive telomere shortening seen in succeeding generations (Nat Gen2004; 36:447). We describe here a novel hTERC mutation, with affected individuals presenting in adulthood with mild mucocutaneous abnormalities, bone marrow failure and a pattern of penetrance supporting the presence of disease anticipation. The proband in the family studied presented at age 49 with squamous cell carcinoma of the tongue and a history of oral leukoplakia which he had developed at age 30. Peripheral blood on presentation was remarkable only for a mild macrocytic anemia. During treatment of his malignancy, severe and irreversible bone marrow hypoplasia was precipitated by a single cycle of cisplatinum chemotherapy. The patient’s brother at age 25 had been previously diagnosed with severe aplastic anemia; this was refractory to standard immunosuppression with cyclosporine and antithymocyte globulin. No somatic abnormailites were identified in this patient. Testing for Fanconi anemia in both siblings was negative. Direct sequencing analysis of hTERC in these patients revealed both to be heterozygous for a novel hTERC mutation (79 deletion C). Further studies among family members documented heterozygosity for the mutation in the mother of these two siblings. At age 77, she displayed none of the mucocutaneous signs associated with DC, while the only abnormality seen in her peripheral blood was an elevated mean corpuscular volume. The hTERC mutation seen in this family most likely exerts its effects through disruption of the pseudoknot domain. The findings of an individual with normal longevity, minimal phenotypic expression and affected offspring are further evidence of genetic anticipation being an important feature of autosomal dominant DC. Correlation with determination of telomere length has been initiated.

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de la Guardia, Rafael Díaz, Carolina Elosua, Purificación Catalina, Brian A. Walker, David C. Johnson, David Gonzalez, Faith E. Davies, Gareth J. Morgan, and Paola Leone. "Expression Profile and up-Regulation of Telomere-Associated Proteins In Multiple Myeloma." Blood 116, no. 21 (November 19, 2010): 4050. http://dx.doi.org/10.1182/blood.v116.21.4050.4050.

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Abstract Abstract 4050 The role of the telomeres in the mechanisms of ageing and carcinogenesis has generated a considerable interest as a novel approach to the treatment of many cancers. Telomeres are nucleoproteins structures that protect the ends of eukaryotic chromosomes, which are particularly vulnerable due to progressive shortening in almost all dividing cells. The telomere length was observed as a critical factor in the initiation and progression of human cancers, and it is associated to chromosomal instability. Most immortal cells possess enzymatic activity of telomerase. This suggests that telomerase activity and telomere length maintenance may be required for unlimited cell proliferation, tumorigenesis, and protection, allowing the evasion of apoptosis in cancer development. The telomerase activity could also be regulated positively or negatively by post-trancriptional and/or post-translational modification of the enzyme without transcriptional up-regulation of human telomerase reverse transcriptase (hTERT) mRNA. In this work, we analyze the expression data of all genes involved in telomerase activity. Patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering multiple myeloma (SMM), multiple myeloma (MM) and plasma cell leukemia (PLC) were studied through gene expression profiling analysis (Human Genome U133 Plus 2.0 arrays, Affymetrix). We identify 21 deregulated genes, implicated directly in telomere length maintenance activity in clonal plasma cells compared with normal cells (20 up-regulated and 1 down-regulated). These genes are MYC, KRAS, HSPA9, RB1 and members of the families: Small nucleolar ribonucleoproteins (H/ACA snoRNPs), A/B subfamily of ubiquitously expressed heterogeneous nuclear ribonucleoproteins (hnRNPs), and 14-3 -3 family. In conclusion, the myeloma cells acquire the telomere maintenance capability without deregulation of the human telomerase RNA gene (hTERC) and hTERT gene expression. It is an alternative lengthening of telomeres mechanism that has effect in the regulation of the BAD activity in apoptosis. The mechanism is based on preventing the partially-denatured proteins from aggregating, telomere maintenance through the correct processing and intranuclear trafficking of hTERC, telomerase reactivation and telomere stabilization, and efficient accumulation of hTERT in the nucleus. Thus, the findings of this study may help to improve telomerase-based therapy for multiple myeloma. Disclosures: No relevant conflicts of interest to declare.

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Takeuchi, Junko, Ly Hinh, Beauchamp Adam, Koiti Inokuchi, Fumiko Kosaka, Kazuhiro Sawaguchi, Yoshio Mitamura, et al. "Identification and Functional Characterization of Telomerase RNA Variant Alleles in Japanese Patients with Aplastic Anemia or Myelodysplastic Syndrome." Blood 108, no. 11 (November 16, 2006): 977. http://dx.doi.org/10.1182/blood.v108.11.977.977.

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Abstract Dyskeratosis Congenita (DKC) is an inherited bone marrow failure (BMF) characterized by abnormal skin pigmentation, nail dystrophy and mucosa leucoplakia. Mutations in the DKC1 and TERC genes occur in the X-linked and autosomal dominant DKC, respectively. Several groups have recently reported that mutations of the telomerase TERC RNA and of the telomerase catalytic TERT protein caused short telomere and developed DKC and other BMF syndromes, such as aplastic anemia (AA) and myelodysplasia (MDS). As the incidence for BMF seems to be higher in East Asia than in the West, we investigated whether mutations in TERC and TERT genes are indeed associated with BMF patients in Japan. We examined blood or marrow cells from 73 BMF patients; 27 samples collected from patients with acquired AA (n=27) who did not respond to immunosuppressive therapy, and 46 samples from patients with MDS (RA). We also analyzed blood samples from 120 healthy donors as controls. Polymerase-chain-reaction (PCR) amplification of TERC and TERT genes was performed with DNA samples extracted from peripheral blood or bone marrow cells. PCR products were purified and direct sequencing was performed. Altered sequences were transfected into telomerase-negative cell line in order to address the effect of the mutations on telomerase enzymatic function. We found two polymorphic sequence changes (n-717A/G and n-713 deletion) in the promoter region of the hTERC gene and nine TERT polymorphic sequences in the hTERT gene. These hTERT sequence polymorphisms, which were also identified in healthy individuals, did not introduce an amino acid change in the corresponding protein. To our knowledge, the two TERC polymorphisms and three of the nine TERT polymorphisms (IVS6 −93 G/A, codon837 CTC/CTG and codon 840 CTG/CTA) have not been reported elsewhere. Among the 73 BMF patients, 1(1.4%) heterozygous TERC mutation (C323T) was identified in an MDS patient. This mutation was not observed in normal controls. The C323T mutation is located on the P5 stem of the predicted hTERC RNA secondary structure, which suggests that the mutation may disrupt basepairing interactions of this stem. We introduced this C233T mutation, as well as additional sequence changes to test for the effect of the mutation in the formation of the P5 stem, into VA13+hTERT cells. We found that the mutations located on the individual strands of the P5 stem (either the natural C323T(rt) mutation or the corresponding C323T(lt) mutation located at position 246 alone) abolished telomerase activity to about the same degree. Interestingly, the compensatory mutation (C323T(comp)), in which the natural C323T mutation was accompanied by complementary mutation on the opposite strand of the P5 stem, did not restore telomerase activity, suggesting that both the primary and secondary structure of the P5 stem are important to confer optimal telomerase enzymatic activity. Moreover, no effects were observed between cells that carried only the wild type TERC vector and those that carried both the wild type and the individual mutated TERC copy. These results suggest that the natural hTERC variant functions in a haploinsufficient manner to modulate wild type telomerase function.

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Hiroi, Sadayuki, Kuniaki Nakanishi, and Toshiaki Kawai. "Expressions of human telomerase mRNA component (hTERC) and telomerase reverse transcriptase (hTERT) mRNA in effusion cytology." Diagnostic Cytopathology 29, no. 4 (September 18, 2003): 212–16. http://dx.doi.org/10.1002/dc.10352.

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Lirussi, Lisa, and Hilde Nilsen. "Telomere maintenance: regulating hTERC fate through RNA modifications." Molecular & Cellular Oncology 6, no. 6 (October 15, 2019): e1670489. http://dx.doi.org/10.1080/23723556.2019.1670489.

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Chen, Min, and Li-Na Xing. "siRNA-mediated Inhibition of hTERC Enhances Radiosensitivity of Cervical Cancer." Asian Pacific Journal of Cancer Prevention 13, no. 12 (December 31, 2012): 5975–79. http://dx.doi.org/10.7314/apjcp.2012.13.12.5975.

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Harada, Kunyu, Kaoru Kurisu, Hidetoshi Tahara, Eiji Tahara, Toshinori Ide, and Eiichi Tahara. "Telomerase activity in primary and secondary glioblastomas multiforme as a novel molecular tumor marker." Journal of Neurosurgery 93, no. 4 (October 2000): 618–25. http://dx.doi.org/10.3171/jns.2000.93.4.0618.

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Object. Telomerase activity is responsible for cell immortality. To examine the role of telomerase in the carcinogenesis of human glioblastomas multiforme (GBMs), the authors studied telomerase activity, telomerase component expression, and telomere lengths in 42 GBM samples.Methods. In all samples, EGFR and MDM2 amplifications and overexpressions were examined using Southern and Northern blot analyses. The p53 mutation was analyzed using polymerase chain reaction—single strand conformational polymorphism and by direct sequence analysis. Specimens of tissues were immunostained with p53, EGFR, and MDM2 antibodies. Allelic loss on chromosomes 17p and 10 was assessed by loss of heterozygosity (LOH) assays. Telomerase activity, expression of its components (human telomerase reverse transcriptase [hTERT], human telomerase RNA component [hTERC], and telomerase-associated protein [TEP1]), and telomere lengths were analyzed using the telomeric repeat amplification protocol (TRAP)—hybridization protection assay, reverse transcription—polymerase chain reaction, and Southern blot analysis. According to the results of assessments of EGFR and MDM2 amplifications, p53 mutation, LOHs in chromosomes 17p and 10, and the clinical course of the disease, the 42 samples were classified into 22 primary and 20 secondary glioblastomas.Twenty-six (61.9%) of all 42 samples demonstrated detectable telomerase activity during the TRAP assay. Secondary GBMs displayed significantly higher levels of telomerase activity and hTERT expression than primary GBMs. Tumors with a p53 gene mutation demonstrated significantly higher telomerase activity than those without a p53 mutation. Four samples with a codon 175 mutation demonstrated an exceptionally high amount of telomerase activity. In secondary GBMs, the increase in telomerase activity and the hTERT expression level correlated with the increased frequency of p53 mutations. There was no significant difference in telomere length between primary and secondary GBMs.Conclusions. These results suggest that telomerase activity and p53 mutations both play important roles in the multistep carcinogenesis of GBMs. Telomerase activity and hTERT expression may be considered as novel distinctive factors in human GBMs.

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Ahmad, Nadhirah, Joo Jie Ching, and Nazia Abdul Majid. "Investigation of Boldine as a Potential Telomerase Inhibitor by Downregulation of hTERT/hTERC in HCT 116 Human Colon Carcinoma Cells." Sains Malaysiana 48, no. 9 (September 30, 2019): 1833–40. http://dx.doi.org/10.17576/jsm-2019-4809-04.

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Umar, Mubarak I., and Chun Kit Kwok. "Specific suppression of D-RNA G-quadruplex–protein interaction with an L-RNA aptamer." Nucleic Acids Research 48, no. 18 (September 25, 2020): 10125–41. http://dx.doi.org/10.1093/nar/gkaa759.

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Abstract G-quadruplexes (G4s) are nucleic acid structure motifs that are of significance in chemistry and biology. The function of G4s is often governed by their interaction with G4-binding proteins. Few categories of G4-specific tools have been developed to inhibit G4–protein interactions; however, until now there is no aptamer tool being developed to do so. Herein, we present a novel L-RNA aptamer that can generally bind to D-RNA G-quadruplex (rG4) structure, and interfere with rG4–protein interaction. Using hTERC rG4 as the target for in vitro selection, we report the shortest L-aptamer being developed so far, with only 25 nucleotides. Notably, this new aptamer, L-Apt.4-1c, adopts a stem–loop structure with the loop folding into an rG4 motif with two G-quartet, demonstrates preferential binding toward rG4s over non-G4s and DNA G-quadruplexes (dG4s), and suppresses hTERC rG4–nucleolin interactions. We also show that inhibition of rG4–protein interaction using L-RNA aptamer L-Apt.4-1c is comparable to or better than G4-specific ligands such as carboxypyridostatin and QUMA-1 respectively, highlighting that our approach and findings expand the current G4 toolbox, and open a new avenue for diverse applications.

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Laye, Matthew J., Thomas P. J. Solomon, Kristian Karstoft, Karin K. Pedersen, Susanne D. Nielsen, and Bente K. Pedersen. "Increased shelterin mRNA expression in peripheral blood mononuclear cells and skeletal muscle following an ultra-long-distance running event." Journal of Applied Physiology 112, no. 5 (March 1, 2012): 773–81. http://dx.doi.org/10.1152/japplphysiol.00997.2011.

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Located at the end of chromosomes, telomeres are progressively shortened with each replication of DNA during aging. Integral to the regulation of telomere length is a group of proteins making up the shelterin complex, whose tissue-specific function during physiological stress is not well understood. In this study, we examine the mRNA and protein levels of proteins within and associated with the shelterin complex in subjects ( n = 8, mean age = 44 yr) who completed a physiological stress of seven marathons in 7 days. Twenty-two to 24 h after the last marathon, subjects had increased mRNA levels of DNA repair enzymes Ku70 and Ku80 ( P < 0.05) in both skeletal muscle and peripheral blood mononuclear cells (PBMCs). Additionally, the PBMCs displayed an increment in three shelterin protein mRNA levels (TRF1, TRF2, and Pot-1, P < 0.05) following the event. Seven days of ultrarunning did not result in changes in mean telomere length, telomerase activity, hTert mRNA, or hterc mRNAs found in PBMCs. Higher protein concentrations of TRF2 were found in skeletal muscle vs. PBMCs at rest. Mean telomere length in skeletal muscle did not change and did not contain detectable levels of htert mRNA or telomerase activity. Furthermore, changes in the PBMCs could not be attributed to changes in the proportion of subtypes of CD4+ or CD8+ cells. We have provided the first evidence that, in humans, proteins within and associated with the shelterin complex increase at the mRNA level in response to a physiological stress differentially in PBMCs and skeletal muscle.

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Hu, Yanping, Xiaojing Teng, Linlin Wu, Wei Liu, and Jianduo An. "The Clinicopathological Correlations of hTERC Amplification with Esophageal Squamous Cell Precursor Lesions." Digestive Diseases and Sciences 64, no. 1 (October 11, 2018): 68–75. http://dx.doi.org/10.1007/s10620-018-5318-7.

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Diala, Irmina, Yasuo Shiohama, Takashi Fujita, Yojiro Kotake, Constantinos Demonacos, Marija Krstic-Demonacos, Gianpiero Di Leva, and Masayuki Fujii. "Telomerase inhibition, telomere attrition and proliferation arrest of cancer cells induced by phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT." Nucleosides, Nucleotides & Nucleic Acids 39, no. 1-3 (February 20, 2020): 407–25. http://dx.doi.org/10.1080/15257770.2020.1713357.

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23

Nishio, Yuko, Kuniaki Nakanishi, Yuichi Ozeki, Shi-Xu Jiang, Toru Kameya, Akira Hebisawa, Makio Mukai, William D. Travis, Teri J. Franks, and Toshiaki Kawai. "Telomere Length, Telomerase Activity, and Expressions of Human Telomerase mRNA Component (hTERC) and Human Telomerase Reverse Transcriptase (hTERT) mRNA in Pulmonary Neuroendocrine Tumors." Japanese Journal of Clinical Oncology 37, no. 1 (October 23, 2006): 16–22. http://dx.doi.org/10.1093/jjco/hyl118.

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Dorji, Tshering, Valentina Monti, Giovanni Fellegara, Silvia Gabba, Vittorio Grazioli, Elena Repetti, Chiara Marcialis, et al. "Gain of hTERC: a genetic marker of malignancy in oral potentially malignant lesions." Human Pathology 46, no. 9 (September 2015): 1275–81. http://dx.doi.org/10.1016/j.humpath.2015.05.013.

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Guo, Qisang, Long Sui, and Youji Feng. "Cervical cancer screening: hTERC gene amplification detection by FISH in comparison with conventional methods." Open Journal of Obstetrics and Gynecology 02, no. 01 (2012): 11–17. http://dx.doi.org/10.4236/ojog.2012.21003.

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26

Ozer, Ozge, Tugce Bulakbasi Balci, Zerrin Yilmaz, and Feride Iffet Sahin. "Fluorescence in situ hybridization analysis of the hTERC region in acute myeloid leukemia patients." Turkish Journal of Hematology 28, no. 2 (June 1, 2011): 103–6. http://dx.doi.org/10.5152/tjh.2011.25.

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27

Ohyashiki, K., Y. Ishii, S. Honda, G. Sashida, Y. Zhang, and J. H. Ohyashiki. "P-47 Lack of mutations of the humantelomerase RNA gene (HTERC) in myelodysplastic syndromes." Leukemia Research 29 (January 2005): S42. http://dx.doi.org/10.1016/s0145-2126(05)80111-0.

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Li, Ying, Wen-Jie Zeng, Feng Ye, Xin-Yu Wang, Wei-Guo Lü, Ding Ma, Li-Hui Wei, and Xing Xie. "Application of hTERC in thinprep samples with mild cytologic abnormality and HR-HPV positive." Gynecologic Oncology 120, no. 1 (January 2011): 73–83. http://dx.doi.org/10.1016/j.ygyno.2010.10.007.

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29

Gros, Julien, Aurore Guédin, Jean-Louis Mergny, and Laurent Lacroix. "G-Quadruplex Formation Interferes with P1 Helix Formation in the RNA Component of Telomerase hTERC." ChemBioChem 9, no. 13 (September 1, 2008): 2075–79. http://dx.doi.org/10.1002/cbic.200800300.

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30

He, Chunnian, Cuiqing Xu, Mingtang Xu, Yanlong Yuan, Yuning Sun, Huanfen Zhao, and Xiuzhi Zhang. "Genomic Amplification of hTERC in Paraffin-embedded Tissues of Cervical Intraepithelial Neoplasia and Invasive Cancer." International Journal of Gynecological Pathology 31, no. 3 (May 2012): 280–85. http://dx.doi.org/10.1097/pgp.0b013e318237d50a.

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31

杨, 梅. "Research on Expression of Telomerase hTERC Gene and Infection of High Risk HPV in Cervix." Asian Case Reports in Oncology 07, no. 04 (2018): 51–55. http://dx.doi.org/10.12677/acrpo.2018.74008.

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32

Zhang, Yuan, Xiaobei Wang, Ling Ma, Zehua Wang, and Lihua Hu. "Clinical significance of hTERC gene amplification detection by FISH in the screening of cervical lesions." Journal of Huazhong University of Science and Technology [Medical Sciences] 29, no. 3 (June 2009): 368–71. http://dx.doi.org/10.1007/s11596-009-0321-z.

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33

Folini, Marco, Cinzia Brambilla, Raffaella Villa, Paolo Gandellini, Sara Vignati, Francesco Paduano, Maria Grazia Daidone, and Nadia Zaffaroni. "Antisense oligonucleotide-mediated inhibition of hTERT, but not hTERC, induces rapid cell growth decline and apoptosis in the absence of telomere shortening in human prostate cancer cells." European Journal of Cancer 41, no. 4 (March 2005): 624–34. http://dx.doi.org/10.1016/j.ejca.2004.12.002.

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34

Brümmendorf, Tim H., Patrick Ziegler, Jamil Akkad, Ute Brassat, Lucia Vankann, Jens Panse, Stefan Wilop, et al. "Telomere Elongation In Vivo and Clinical Response Upon Androgen Treatment in a Patient with Aplastic Anemia and a Heterozygous hTERT Gene Mutation,." Blood 118, no. 21 (November 18, 2011): 3427. http://dx.doi.org/10.1182/blood.v118.21.3427.3427.

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Abstract Abstract 3427 Telomere length both reflects and limits the replicative life-span of normal somatic cells and critically shortened telomeres are associated with a variety of disease states. In patients with aplastic anemia telomere lengths in granulocytes and lymphocytes can be found to be significantly shorter as compared to age-adjusted controls. Telomere shortening in peripheral blood cells therby mirrors telomere shortening in the underlying hematopoietic stem cell reserve, which can be severely diminished in acquired bone marrow failure syndromes. Genetic aberrations such as mutations in the gene for dyskerin or in subunits of the telomerase-complex such as the RNA subunit hTERC or mutations in the human telomerase gene (hTERT) have been described and linked to critically short telomeres found in blood cells. We report here on a 51 year old male patient with moderate aplastic anemia (AA) and a non-synonymous variation of codon 1062 of the hTERT gene (pAla1062Thr). Cells with deficient expression of glycosylphosphatidylinositol-anchored proteins (GPI-AP), i.e. cells with a PNH phenotype, were detected (1.2% of erythrocytes, 8% of reticulocytes and 15% of neutrophils). The patient was found to have dramatically shortened telomere length below 1% percentile of normal individuals both in lymphocytes (4.28 +/− 0.02 kbp) and granulocytes (4.14 +/−0.1 kbp). Based on the clinical presentation (i.e. predominance of red blood cell transfusion dependence and thrombocytopenia, but absence of immediate risk e.g. of infections or bleeding) we decided to initiate androgen treatment rather than to initiate standard immunosuppression. The initially red blood cell transfusion dependent and thrombocytopenic patient became completely red blood cell transfusion independent after twelve months of ongoing androgen treatment. A significant proportion of GPI-AP deficient red cells and reticulocytes could no longer be detected and only a very small proportion of GPI-AP deficient granulocytes (<1%) persisted. The clinical and hematological improvement during androgen therapy was mirrored by a continuous and persistent lengthening of telomere length in total peripheral blood mononuclear cells (MNCs) measured by qPCR as well as in both leukocyte subpopulations measured by Flow-FISH. To our knowledge, this represents the first case of sustained telomere elongation in hematopoietic stem cells induced by a pharmacological approach in vivo. Disclosures: No relevant conflicts of interest to declare.

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35

LI, TIAN, LIANGDAN TANG, DUHONG BIAN, YING JIA, XIN HUANG, and XINHUA ZHANG. "Detection of hTERC and c-MYC genes in cervical epithelial exfoliated cells for cervical cancer screening." International Journal of Molecular Medicine 33, no. 5 (March 14, 2014): 1289–97. http://dx.doi.org/10.3892/ijmm.2014.1699.

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36

Rinn, John L., and Howard Y. Chang. "Long Noncoding RNAs: Molecular Modalities to Organismal Functions." Annual Review of Biochemistry 89, no. 1 (June 20, 2020): 283–308. http://dx.doi.org/10.1146/annurev-biochem-062917-012708.

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We have known for decades that long noncoding RNAs (lncRNAs) can play essential functions across most forms of life. The maintenance of chromosome length requires an lncRNA (e.g., hTERC) and two lncRNAs in the ribosome that are required for protein synthesis. Thus, lncRNAs can represent powerful RNA machines. More recently, it has become clear that mammalian genomes encode thousands more lncRNAs. Thus, we raise the question: Which, if any, of these lncRNAs could also represent RNA-based machines? Here we synthesize studies that are beginning to address this question by investigating fundamental properties of lncRNA genes, revealing new insights into the RNA structure–function relationship, determining cis- and trans-acting lncRNAs in vivo, and generating new developments in high-throughput screening used to identify functional lncRNAs. Overall, these findings provide a context toward understanding the molecular grammar underlying lncRNA biology.

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Danzy, S., C.-y. Su, S. Park, S.-y. Li, A. M. Ferraris, and H. Ly. "Absence of pathogenic mutations of the human telomerase RNA gene (hTERC) in patients with chronic myeloproliferative disorders." Leukemia 20, no. 5 (March 2, 2006): 893–94. http://dx.doi.org/10.1038/sj.leu.2404159.

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38

Guilleret, I. "The human telomerase RNA gene (hTERC) is regulated during carcinogenesis but is not dependent on DNA methylation." Carcinogenesis 23, no. 12 (December 1, 2002): 2025–30. http://dx.doi.org/10.1093/carcin/23.12.2025.

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39

Kokalj Vokač, Nadja, Bogdan Čizmarević, Andreja Zagorac, Boris Zagradišnik, and Boštjan Lanišnik. "An evaluation of SOX2 and hTERC gene amplifications as screening markers in oral and oropharyngeal squamous cell carcinomas." Molecular Cytogenetics 7, no. 1 (2014): 5. http://dx.doi.org/10.1186/1755-8166-7-5.

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40

Glasspool, Rosalind M., Sharon Burns, Stacey F. Hoare, Catharina Svensson, and W. Nicol Keith. "The hTERT and hTERC Telomerase Gene Promoters Are Activated by the Second Exon of the Adenoviral Protein, E1 A, Identifying the Transcriptional Corepressor CtBP as a Potential Rearessor of Both Genes." Neoplasia 7, no. 6 (June 2005): 614–22. http://dx.doi.org/10.1593/neo.04766.

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41

Moukova, Lucie, Vladimira Vranova, Iva Slamova, Miroslava Kissova, and Petr Kuglik. "Initial Experience with Determination of hTERC and MYCC Amplification in Cervical Intraepithelial Neoplasia and Cervical Carcinoma in the Czech Republic." European Oncology & Haematology 08, no. 02 (2012): 92. http://dx.doi.org/10.17925/eoh.2012.08.02.92.

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Tumours are frequently characterised by series of cytogenetic abnormalities. Amplifications of the human telomerase gene hTERC (3q26) and myelocytomatosis-C proto-oncogeneMYCC(8q24) have been associated with cervical intraepithelial neoplasia (CIN) and carcinoma of the uterine cervix. The results of genetic analysis allow to select patients at high risk of progression from CIN to carcinoma. Our group conducted a study in which the chromosomal abnormalities found in the cytology specimens of 26 patients with either cervical cancer or CIN were analysed using the recently developed triple-colour human papillomavirus-fluorescencein situhybridisation (HPV-FISH) assay. HPV infection was proven in 22 (85 %) patients. Amplification ofMYCCandhTERCwas found in 11 (42 %) and 16 (62 %) patients, respectively. Based on these results, the patients were divided into high-risk, medium-risk and low-risk groups. The study confirmed that the HPV-FISH assay can be used as an effective diagnostic procedure to identify patients carrying high-risk HPV infection and chromosomal aberrations associated with the development of malignancy. Patients in the high-risk group would require more frequent folllow-up and aggressive therapy.

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42

Martadinata, Herry, and Anh Tuân Phan. "Formation of a Stacked Dimeric G-Quadruplex Containing Bulges by the 5′-Terminal Region of Human Telomerase RNA (hTERC)." Biochemistry 53, no. 10 (March 6, 2014): 1595–600. http://dx.doi.org/10.1021/bi4015727.

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43

Wu, R. "O1005 The amplification and clinical significance of hTERC gene in the cervical exfoliated cells from natural population in Shenzhen." International Journal of Gynecology & Obstetrics 107 (October 2009): S379. http://dx.doi.org/10.1016/s0020-7292(09)61378-3.

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44

Panero, Julieta, Dorotea Beatriz Fantl, Jorge Arbelbide, and Irma Slavutsky. "Non-Shelterin Telomere Genes Deregulation in Plasma Cell Disorders." Blood 124, no. 21 (December 6, 2014): 2020. http://dx.doi.org/10.1182/blood.v124.21.2020.2020.

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Abstract Telomeres are essential structures that protect the ends of linear chromosomes. When telomeres become dysfunctional, critically short ends are sensed by the DNA repair machinery triggering senescence or apoptosis as well as creating interchromosomal fusions. Telomere structure and functions depend on the telomerase enzyme (hTERT, hTERC and DKC1) for elongation, on the sheterin complex that regulates telomere length (TL) and protects them against degradation and fusion, and on the non-shelterin complex. The latter is constituted by a set of multifunctional factors, including RPA1 and the MRE11-RAD50-NBS1 (MRN) complex, that facilitate telomerase-based telomere elongation. Particularly, RPA1 might be a crucial link between telomere homeostasis and the replication of chromosome ends as it regulate the telomerase action during the cell cycle. The role of MRN complex in telomere maintenance parallels its function in DNA repair. In telomerase-positive cells, a reduction of the MRN complex results in G-overhang shortening, suggesting MRN complex involvement in the recruitment or action of telomerase. Previous data from our group have provided the first evidence of modifications in the mRNA expression of shelterin members in plasma cell disorders (Panero et al, Mol Med 2010; 16: 471-8; Blood Cells Mol Dis 2014; 52: 134-9). The aim of the present study was to examine the expression profile of the non-shelterin complex: RPA1, RAD50, MRE11, NBS1 and DKC1 in patients with multiple myeloma (MM) and monoclonal gammopathy of undetermined significance (MGUS). Results were correlated with hTERT (telomerase catalytic subunit) mRNA levels, TL, and clinico-pathological characteristics of patients. Bone marrow samples from 70 cases: 35 MM (21 females; mean age: 67.9 years; range: 30-87 years; 35.3% stage III) and 35 MGUS (21 females; mean age: 68.7 years; range: 39-88 years) were studied. All patients gave informed consent and the study was approved by the Ethics Committee of our Institution. Gene expression was quantified by Real-time Quantitative PCR, using Taq-Man methodology, and TL measurements were performed by Terminal Restriction Fragments. A significant increase in the mean mRNA levels of all non-shelterin genes in patients with MM respect to cases with MGUS was observed (Table 1). In order to evaluate whether the expression of these factors was associated to telomerase activity, hTERT transcripts were also quantified. An upregulation of telomerase expression, with significant differences between entities was found (p=0.03). In MM, higher DKC1 mRNA levels (0.10±0.02) in patients who over-expressed telomerase compared to patients with low hTERT expression (0.04±0.004) (p=0.008) was observed. No association between gene expression and TL or clinical parameters was found. To the best of our knowledge, our findings show for the first time a global modification in the expression of non-shelterin genes in MM and MGUS, suggesting that their upregulation in MM may occur as a result of the increasing need for DNA repair and telomerase recruitment, contributing to the progression of the disease. In addition, DKC1 was related to hTERTlevels in MM patients, supporting the role that DKC1 plays in telomerase complex stabilization and telomere maintenance. Table 1. Expression profile of non-shelterin genes in patients with plasma cell disorders Genes MGUS (X±ES) MM (X±ES) p value DKC1 0.036±0.003 0.052±0.005 0.02 RAD50 0.060±0.007 0.237±0.064 0.0001 MRE11 0.277±0.040 0.545±0.114 0.003 NBS1 0.448±0.066 0.894±0.148 0.02 RPA1 0.391±0.044 0.591±0.082 0.02 Disclosures No relevant conflicts of interest to declare.

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45

Wang, Xiaobin, Jia Liu, Hong Xi, and Liping Cai. "The significant diagnostic value of human telomerase RNA component (hTERC) gene detection in high-grade cervical lesions and invasive cancer." Tumor Biology 35, no. 7 (April 16, 2014): 6893–900. http://dx.doi.org/10.1007/s13277-014-1915-z.

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46

Aggarwal, Divya, Neelam Wadhwa, Tanvi Arora, Shalini Rajaram, Preeti Diwaker, Ashutosh Halder, Manish Jain, and Kiran Mishra. "Human telomerase RNA component (hTERC) gene expression and chromosome 7 ploidy correlate positively with histological grade of cervical intraepithelial neoplasia." Cytopathology 32, no. 5 (April 13, 2021): 631–39. http://dx.doi.org/10.1111/cyt.12978.

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47

Beattie, Tara L., Wen Zhou, Murray O. Robinson, and Lea Harrington. "Polymerization Defects within Human Telomerase Are Distinct from Telomerase RNA and TEP1 Binding." Molecular Biology of the Cell 11, no. 10 (October 2000): 3329–40. http://dx.doi.org/10.1091/mbc.11.10.3329.

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The minimal, active core of human telomerase is postulated to contain two components, the telomerase RNA hTER and the telomerase reverse transcriptase hTERT. The reconstitution of human telomerase activity in vitro has facilitated the identification of sequences within the telomerase RNA and the RT motifs of hTERT that are essential for telomerase activity. However, the precise role of residues outside the RT domain of hTERT is unknown. Here we have delineated several regions within hTERT that are important for telomerase catalysis, primer use, and interaction with the telomerase RNA and the telomerase-associated protein TEP1. In particular, certain deletions of the amino and carboxy terminus of hTERT that retained an interaction with telomerase RNA and TEP1 were nonetheless completely inactive in vitro and in vivo. Furthermore, hTERT truncations lacking the amino terminus that were competent to bind the telomerase RNA were severely compromised for the ability to elongate telomeric and nontelomeric primers. These results suggest that the interaction of telomerase RNA with hTERT can be functionally uncoupled from polymerization, and that there are regions outside the RT domain of hTERT that are critical for telomerase activity and primer use. These results establish that the human telomerase RT possesses unique polymerization determinants that distinguish it from other RTs.

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48

Martadinata, Herry, and Anh Tuân Phan. "Correction to Formation of a Stacked Dimeric G-Quadruplex Containing Bulges by the 5′-Terminal Region of Human Telomerase RNA (hTERC)." Biochemistry 54, no. 48 (November 25, 2015): 7156. http://dx.doi.org/10.1021/acs.biochem.5b01231.

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49

Alameda, Francesc, Blanca Espinet, Cristina Corzo, Raquel Muñoz, Beatriz Bellosillo, Belén Lloveras, Lara Pijuan, et al. "3q26 (hTERC) gain studied by fluorescence in situ hybridization as a persistence-progression indicator in low-grade squamous intraepithelial lesion cases." Human Pathology 40, no. 10 (October 2009): 1474–78. http://dx.doi.org/10.1016/j.humpath.2009.03.013.

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50

保, 丽玲, and 悦. 陆. "宫颈癌及癌前病变组织hTERC基因表达及其临床意义." 亚洲临床医学杂志 4, no. 3 (April 26, 2021): 64. http://dx.doi.org/10.26549/yzlcyxzz.v4i3.6893.

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