scholarly journals Evaluations of short telomere risk-associated single nucleotide polymorphisms in telomerase reverse transcriptase gene on telomere length maintenance

2019 ◽  
Author(s):  
Jialin Xu ◽  
Matthew A. Trudeau ◽  
Andrew J. Sandford ◽  
Judy M.Y. Wong
Keyword(s):  
Single Nucleotide Polymorphisms ◽  
Reverse Transcriptase ◽  
Telomere Length ◽  
Replicative Senescence ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Nucleotide Polymorphisms ◽  
Primary Cells ◽  
Single Nucleotide ◽  
Telomere Biology

ABSTRACTTelomere biology disorders (TBDs) refer to a spectrum of tissue degenerative disorders caused by genetic mutations in telomere biology genes. Most patients with TBDs suffer from telomere maintenance defects secondary to telomerase deficiency. While the highly penetrant mutations in the telomerase reverse transcriptase (TERT) gene that drive disease onset and progression of TBDs are relatively rare, there exist several single nucleotide polymorphisms (SNPs) in TERT that have been linked to various diseases in the TBD spectrum. In this study, we investigated the biochemical properties of five TERT variants. In an ex vivo cell model, we found that primary human fibroblasts expressing nonsynonymous TERT SNPs had comparable cell growth kinetics to primary cells expressing WT-TERT, while a parallel vector control expressing-cell line entered replicative senescence. At the molecular level, primary cells expressing the minor alleles of two of the five TERT variants (A279T, ΔE441) had replication-dependent loss of telomere length. In an in vitro primer extension assay, these two variants showed reduced telomerase nucleotide addition processivity. Together, our data suggested that selective, common TERT variants could be revealed to harbour telomere maintenance defects, leading to a plausible explanation for their observed associations to telomere biology disorders.

Non-canonical Functions of Telomerase Reverse Transcriptase: Emerging Roles and Biological Relevance

2020 ◽  
Vol 20 (6) ◽  
pp. 498-507 ◽  
Author(s):  
Connor A.H. Thompson ◽  
Judy M.Y. Wong
Keyword(s):  
Oxidative Stress ◽  
Dna Damage ◽  
Reverse Transcriptase ◽  
Cancer Cells ◽  
Telomere Length ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Alternative Mechanism ◽  
Dependent Manner ◽  
Mitochondrial Integrity

Increasing evidence from research on telomerase suggests that in addition to its catalytic telomere repeat synthesis activity, telomerase may have other biologically important functions. The canonical roles of telomerase are at the telomere ends where they elongate telomeres and maintain genomic stability and cellular lifespan. The catalytic protein component Telomerase Reverse Transcriptase (TERT) is preferentially expressed at high levels in cancer cells despite the existence of an alternative mechanism for telomere maintenance (alternative lengthening of telomeres or ALT). TERT is also expressed at higher levels than necessary for maintaining functional telomere length, suggesting other possible adaptive functions. Emerging non-canonical roles of TERT include regulation of non-telomeric DNA damage responses, promotion of cell growth and proliferation, acceleration of cell cycle kinetics, and control of mitochondrial integrity following oxidative stress. Non-canonical activities of TERT primarily show cellular protective effects, and nuclear TERT has been shown to protect against cell death following double-stranded DNA damage, independent of its role in telomere length maintenance. TERT has been suggested to act as a chromatin modulator and participate in the transcriptional regulation of gene expression. TERT has also been reported to regulate transcript levels through an RNA-dependent RNA Polymerase (RdRP) activity and produce siRNAs in a Dicer-dependent manner. At the mitochondria, TERT is suggested to protect against oxidative stress-induced mtDNA damage and promote mitochondrial integrity. These extra-telomeric functions of TERT may be advantageous in the context of increased proliferation and metabolic stress often found in rapidly-dividing cancer cells. Understanding the spectrum of non-canonical functions of telomerase may have important implications for the rational design of anti-cancer chemotherapeutic drugs.

scholarly journals The leukocyte telomere length, single nucleotide polymorphisms near TERC gene and risk of COPD

PeerJ ◽  
2021 ◽  
Vol 9 ◽  
pp. e12190
Author(s):  
Tanya Tacheva ◽  
Shanbeh Zienolddiny ◽  
Dimo Dimov ◽  
Denitsa Vlaykova ◽  
Tatyana Vlaykova
Keyword(s):  
Oxidative Stress ◽  
Single Nucleotide Polymorphisms ◽  
Telomere Length ◽  
Airflow Obstruction ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Genotype Combination ◽  
Link Type ◽  
Genotype Frequencies ◽  
Copd Patients

Chronic obstructive pulmonary disease (COPD) is characterized by irreversible airflow obstruction and is associated with chronic local and systemic inflammation and oxidative stress. The enhanced oxidative stress and inflammation have been reported to affect telomere length (TL). Furthermore, a number of SNPs at loci encoding the main components of the telomerase genes, TERT and TERC have been shown to correlate with TL. We aimed to explore the leukocyte TL and genotypes for single nucleotide polymorphisms, rs12696304 (C > G) and rs10936599 (C > T) near TERC in COPD cases and matched healthy controls using q-PCR technologies. Successful assessment of TL was performed for 91 patients and 88 controls. The patients had shorter TL (17919.36 ± 1203.01 bp) compared to controls (21 271.48 ± 1891.36 bp) although not significant (p = 0.137). The TL did not associate with the gender, age, spirometric indexes, smoking habits but tended to correlate negatively with BMI (Rho = − 0.215, p = 0.076) in the controls, but not in COPD patients. The genotype frequencies of the SNPs rs12696304 and rs10936599 were compared between patients and controls and the odds ratios (OR) for developing COPD were calculated. The carriers of the common homozygous (CC) genotypes of the SNPs had higher risk for COPD, compared to carriers of the variants alleles (rs12696304 CG+GG vs. CC; OR: 0.615, 95% CI [0.424–0.894], p = 0.011 and for rs10936599 CT+TT vs. CC OR = 0.668, 95% CI [0.457–0.976], p = 0.044). Analysis on the combined effects of the TERC rs12696304 (C > G) and rs10936599 (C > T) genotypes, CC/CC genotype combination was associated with higher risk for COPD (p < 0.0001) and marginally lower FEV1% pr. in patients with GOLD II (p = 0.052). There was no association between the SNP genotypes and TL. In summary, our results suggest that COPD patients may have shorter TL, and rs12696304 and rs10936599 near TERC may affect the risk of COPD independently of TL.

Human Telomerase Reverse Transcriptase (hTERT) Deficiency in Myelodysplastic Syndrome (MDS) Demonstrates Mechanistic Linkage to Aplastic Anemia Pathophysiology

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 791-791
Author(s):  
Lili Yang ◽  
Adam W Mailloux ◽  
Dana E Rollison ◽  
Jong Park ◽  
Jeffrey S. Painter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Reverse Transcriptase ◽  
Aplastic Anemia ◽  
Telomere Length ◽  
Telomerase Activity ◽  
S Phase ◽  
Telomere Maintenance ◽  
Telomerase Reverse Transcriptase ◽  
Htert Transcription

Abstract Abstract 791 Background: Myelodysplastic syndromes (MDS) are characterized by dysregulated myelopoiesis and peripheral cytopenias with enormous disease heterogeneity owing to diverse molecular pathobiology. The early manifestations of MDS, however, are relatively well conserved and include increased apoptosis coupled to excessive proliferation of myeloid progenitors. In addition to myeloid abnormalities, repertoire contraction and memory expansion is demonstrable in T cells. The notion that apoptosis of hematopoetic cells may be triggered through an immune–mediated mechanism arose from similarities with aplastic anemia (AA). Our recent data showed that MDS responsive to immunosuppressive therapy has accelerated naïve T cell turnover (ie, high proliferative index plus excessive cell death) which led us to hypothesize the presence of an inherent T cell abnormality impairing homeostatic regulation. AA can be caused by somatic mutations within telomere repair components. T-cells are one of a few somatic cells that retain telomerase function to control naïve T-cell survival, replication potential, and antigenic diversity. To this end, we examined telomere function and replicative burst capacity of MDS T cells as a possible mechanism for immune dysregulation. Methods: Primary specimens from MDS (n=37), AA (n=8), and controls (n=42) were investigated. Peripheral blood mononuclear cells were isolated from patient blood or buffy coats by Ficoll-Hypaque gradient centrifugation. Purified CD3+ T cells were isolated using negative selection and then stimulated with anti-CD3/anti-CD28 T cell activator beads (Dynabead®) for 3 days. Telomere length was assessed by quantitative PCR (q-PCR) and telomerase enzymatic function measured by Telomere Repeat Amplification Protocol (TRAP) assays. Results: Mean telomere length in purified T cells was significantly shorter among MDS patients compared to controls after adjusting for age and sex (p<0.0001). To assess telomerase repair function in MDS T-cells, we performed TRAP assays with purified T cells after stimulation and found that inducible telomerase activity is severely suppressed in MDS compare to controls. In comparison to controls, the inducible telomerase activity fell below the 95% confidence internal in all cases (MDS median 18.70, 95% CI, 15.93–20.54 vs control median 45.0, 95% CI, 45.79 – 64.5, p<0.0001) and the amount of telomerase activity was unrelated to risk stratification by the International Prognostic Scoring System (IPSS), World Health Organization (WHO) classification, and age indicating that it is a frequent abnormality in the disease. Analysis of telomerase function and telomere length in T cells from patients with AA showed a similar deficiency in telomerase repair function. The mechanism responsible for telomerase insufficiency in MDS was mediated by defective induction of telomerase reverse transcriptase (hTERT) transcription; the key enzyme involved in telomere maintenance. Next, to determine the functional consequences of the disturbance in telomere repair in MDS, the ability of T cells to enter S-phase and to undergo an antigen-induced proliferative burst were examined. TCR signaling was shown to be preserved, evidenced by induction of an early activation antigen CD69. Although some cells were capable of entering S-phase, the replicative burst potential was severely impaired in T cells form all patients. Telomere repair is exclusively present in naïve T cells and progressively declines after memory transition. TCR triggered telomerase activity was measured in sorted naïve (CD45RA+, CD45RO-) and memory (CD45RO+, CD45RA-) T cells. The telomere length in naïve cells was shorter in MDS patients compared to controls (p=0.018) and the telomerase activity was suppressed in naïve MDS T cells (p=0.0207) indicating that telomere dysfunction underlies the altered homeostasis of naïve T cells in MDS, a feature mechanistically akin to AA and other telomere repair disorders. Conclusion: Results of this study indicate that there is loss of telomere maintenance in naïve T cells due to a defect in hTERT transcription is associated with impaired replicative potential. This abnormality in naïve T cell homeostasis represents an inherent defect that contributes to a memory cell growth advantage and repertoire contraction associated with autoimmunity in AA and MDS. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Expression of Telomerase RNA Template, but Not Telomerase Reverse Transcriptase, Is Limiting for Telomere Length Maintenance In Vivo

2004 ◽  
Vol 24 (16) ◽  
pp. 7024-7031 ◽  
Author(s):  
Y. Jeffrey Chiang ◽  
Michael T. Hemann ◽  
Karen S. Hathcock ◽  
Lino Tessarollo ◽  
Lionel Feigenbaum ◽  
...  
Keyword(s):  
Reverse Transcriptase ◽  
Telomere Length ◽  
Telomerase Activity ◽  
Telomere Maintenance ◽  
Gene Copy ◽  
Telomerase Reverse Transcriptase ◽  
Telomerase Rna ◽  
Wild Type ◽  
Telomere Elongation

ABSTRACT Telomerase consists of two essential components, the telomerase RNA template (TR) and telomerase reverse transcriptase (TERT). The haplo-insufficiency of TR was recently shown to cause one form of human dyskeratosis congenita, an inherited disease marked by abnormal telomere shortening. Consistent with this finding, we recently reported that mice heterozygous for inactivation of mouse TR exhibit a similar haplo-insufficiency and are deficient in the ability to elongate telomeres in vivo. To further assess the genetic regulation of telomerase activity, we have compared the abilities of TR-deficient and TERT-deficient mice to maintain or elongate telomeres in interspecies crosses. Homozygous TERT knockout mice had no telomerase activity and failed to maintain telomere length. In contrast, TERT+/− heterozygotes had no detectable defect in telomere elongation compared to wild-type controls, whereas TR+/− heterozygotes were deficient in telomere elongation. Levels of TERT mRNA in heterozygous mice were one-third to one-half the levels expressed in wild-type mice, similar to the reductions in telomerase RNA observed in TR heterozygotes. These findings indicate that both TR and TERT are essential for telomere maintenance and elongation but that gene copy number and transcriptional regulation of TR, but not TERT, are limiting for telomerase activity under the in vivo conditions analyzed.

scholarly journals Single nucleotide polymorphisms in telomere length-related genes are associated with hepatocellular carcinoma risk in the Chinese Han population

2020 ◽  
Vol 12 ◽  
pp. 175883592093302
Author(s):  
Peng Huang ◽  
Rong Li ◽  
Lin Shen ◽  
Weizhou He ◽  
Shuo Chen ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Single Nucleotide Polymorphisms ◽  
Telomere Length ◽  
Chinese Han Population ◽  
Nucleotide Polymorphisms ◽  
Chinese Han ◽  
Single Nucleotide ◽  
Frequency Distributions ◽  
Han Population ◽  
Tert Gene

Background: Single nucleotide polymorphisms (SNPs) in telomere-related genes are associated with a high risk of hepatocellular carcinoma (HCC). In this study, we investigated the SNPs of telomere length-related genes and their correlation with HCC risk in the Chinese Han population. Materials and methods: A total of 473 HCC patients and 564 healthy volunteers were recruited. Overall, 42 SNPs distributed in telomere-related genes were selected and identified. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Results: We found rs6713088 (OR = 1.27, 95% CI = 1.07–1.52, p = 0.007), rs843711 (OR = 1.29, 95% CI = 1.09–1.54, p = 0.004) and rs843706 (OR = 1.30, 95% CI = 1.09–1.55, p = 0.003) in the ACYP2 gene, rs10936599 (OR = 1.21, 95% CI = 1.02–1.44, p = 0.032) in the TERC gene and rs7708392 (OR = 1.24, 95% CI = 1.00–1.52, p = 0.042) in the TNIP1 gene were associated with high HCC risk (OR > 1). In contrast, rs1682111 (OR = 0.77, 95% CI = 0.64–0.94, p = 0.008) in the ACYP2 gene, rs2320615 (OR = 0.79, 95% CI = 0.64–0.99, p = 0.038) in the NAF1 gene, rs10069690 (OR = 0.75, 95% CI = 0.59–0.96, p = 0.021) and rs2242652 (OR = 0.70, 95% CI = 0.55–0.90, p = 0.004) in the TERT gene were associated with low HCC risk (OR < 1). Based on genotype frequency distributions, rs6713088, rs843645, rs843711 and rs843706 located in the ACYP2 gene as well as rs10936599 in the TERC gene were associated with a high incidence of HCC ( p < 0.05). In addition, SNPs in these genes could form a linkage imbalance haplotype. Specifically, the haploid ‘GC’ formed by rs10069690 and rs2242652 within the TERT gene increased the risk of HCC ( p < 0.05). Conclusion: SNPs in ACYP2, TERC, TERT and other genes were correlated with HCC risk in the Chinese Han population. These data may provide new insights into early diagnosis and screening of HCC.

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