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#32959123   2020/09/21 To Up

tRNA ADENOSINE DEAMINASE 3 is required for telomere maintenance in Arabidopsis thaliana.

KEY MESSAGE: tRNA Adenosine Deaminase 3 helps to sustain telomere tracts in a telomerase-independent fashion, likely through regulating cellular metabolism. Telomere length maintenance is influenced by a complex web of chromatin and metabolism-related factors. We previously reported that a lncRNA termed AtTER2 regulates telomerase activity in Arabidopsis thaliana in response to DNA damage. AtTER2 was initially shown to partially overlap with the 5' UTR of the tRNA ADENOSINE DEAMINASE 3 (TAD3) gene. However, updated genome annotation showed that AtTER2 was completely embedded in TAD3, raising the possibility that phenotypes ascribed to AtTER2 could be derived from TAD3. Here we show through strand-specific RNA-Seq, strand-specific qRT-PCR and bioinformatic analyses that AtTER2 does not encode a stable lncRNA. Further examination of the original tad3 (ter2-1/tad3-1) mutant revealed expression of an antisense transcript driven by a cryptic promoter in the T-DNA. Hence, a new hypomorphic allele of TAD3 (tad3-2) was examined. tad3-2 mutants showed hypersensitivity to DNA damage, but no deregulation of telomerase, suggesting that the telomerase phenotype of tad3-1 mutants reflects an off-target effect. Unexpectedly, however, tad3-2 plants displayed progressive loss of telomeric DNA over successive generations that was not accompanied by alteration of terminal architecture or end protection. The phenotype was exacerbated in plants lacking the telomerase processivity factor POT1a, indicating that TAD3 promotes telomere maintenance through a non-canonical, telomerase-independent pathway. The transcriptome of tad3-2 mutants revealed significant dysregulation of genes involved in auxin signaling and glucosinolate biosynthesis, pathways that intersect the stress response, cell cycle regulation and DNA metabolism. These findings indicate that the TAD3 locus indirectly contributes to telomere length homeostasis by altering the metabolic profile in Arabidopsis.
Sreyashree Bose, Ana Victoria Suescún, Jiarui Song, Claudia Castillo-González, Behailu Birhanu Aklilu, Erica Branham, Ryan Lynch, Dorothy E Shippen

2818 related Products with: tRNA ADENOSINE DEAMINASE 3 is required for telomere maintenance in Arabidopsis thaliana.

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#32825005   2020/08/19 To Up

Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy.

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.
Adam Eckburg, Joshua Dein, Joseph Berei, Zachary Schrank, Neelu Puri

2242 related Products with: Oligonucleotides and microRNAs Targeting Telomerase Subunits in Cancer Therapy.



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#32312443   2020/03/06 To Up

A telomerase-responsive nanoprobe with theranostic properties in tumor cells.

Multidrug resistance (MDR) is the main cause of treatment failure in clinical cancer chemotherapy due to the presence of P-glycoproteins (P-gp), which widely exist in stubborn drug-resistant tumor membranes and actively pump drugs from inside the tumor cell to the outside. In this study, we report a novel telomerase-responsive nanoprobe with theranostic properties for inhibiting P-gp expression and reversing MDR by gene silencing. This nanoprobe is composed of an AuNP assembled with telomerase primer, antisense oligonucleotide (ASO), and doxorubicin (Dox). When the designed nanoprobe is uptaken by the MDR cancer cells, the Dox and ASO are specifically released due to the extension of telomerase primer triggered by telomerase. The released ASO specifically hybridizes with multidrug resistance 1 (MDR1) mRNA sequence, which encodes the P-gp. As a result, the expression of P-gp is inhibited and the efflux of Dox is prevented with reduced MDR in cancerous cells. The results demonstrate that the nanoprobe based on telomerase switching for drug release and gene silencing, can both target cancer cells for delivering drugs and overcome the effect of efflux pumps. This work presents a novel paradigm for theranostics of MDR cancer and enhances the efficacy of chemotherapeutics.
He-Hua Zhang, Li-Dong Zhao, Peng Zuo, Bin-Cheng Yin, Bang-Ce Ye

1016 related Products with: A telomerase-responsive nanoprobe with theranostic properties in tumor cells.

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#32310030   // To Up

Telomerase inhibition, telomere attrition and proliferation arrest of cancer cells induced by phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT.

Telomerase activity has been regarded as a critical step in cellular immortalization and carcinogenesis and because of this, regulation of telomerase represents an attractive target for anti-tumor specific therapeutics. Recently, one avenue of cancer research focuses on antisense strategy to target the oncogenes or cancer driver genes, in a sequence specific fashion to down-regulate the expression of the target gene. The protein catalytic subunit, human telomerase reverse transcriptase (hTERT) and the template RNA component (hTERC) are essential for telomerase function, thus theoretically, inhibition of telomerase activity can be achieved by interfering with either the gene expression of hTERT or the hTERC of the telomerase enzymatic complex. The present study showed that phosphorothioate antisense oligonucleotide (sASO)-nuclear localization signal (NLS) peptide conjugates targeting hTERC could inhibit telomerase activity very efficiently at 5 μM concentration but less efficiently at 1 μM concentration. On the other hand, siRNA targeting hTERT mRNA could strongly suppress hTERT expression at 200 nM concentration. It was also revealed that siRNA targeting hTERT could induce telomere attrition and then irreversible arrest of proliferation of cancer cells.
Irmina Diala, Yasuo Shiohama, Takashi Fujita, Yojiro Kotake, Constantinos Demonacos, Marija Krstic-Demonacos, Gianpiero Di Leva, Masayuki Fujii

1097 related Products with: Telomerase inhibition, telomere attrition and proliferation arrest of cancer cells induced by phosphorothioate ASO-NLS conjugates targeting hTERC and siRNAs targeting hTERT.

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#32303682   2020/04/17 To Up

Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome.

Approximately half of all cases of Hoyeraal-Hreidarsson syndrome (HHS), a multisystem disorder characterized by bone marrow failure, developmental defects and very short telomeres, are caused by germline mutations in genes related to telomere biology. However, the varying symptoms and severity of the disease indicate that additional mechanisms are involved. Here, a 3-year-old boy with HHS was found to carry biallelic germline mutations in WRAP53 (WD40 encoding RNA antisense to p53), that altered two highly conserved amino acids (L283F and R398W) in the WD40 scaffold domain of the protein encoded. WRAP53β (also known as TCAB1 or WDR79) is involved in intracellular trafficking of telomerase, Cajal body functions and DNA repair. We found that both mutations cause destabilization, mislocalization and faulty interactions of WRAP53β, defects linked to misfolding by the TRiC chaperonin complex. Consequently, WRAP53β HHS mutants cannot elongate telomeres, maintain Cajal bodies or repair DNA double-strand breaks. These findings provide a molecular explanation for the pathogenesis underlying WRAP53β-associated HHS and highlight the potential contribution of DNA damage and/or defects in Cajal bodies to the early onset and/or severity of this disease.
Sofie Bergstrand, Stefanie Böhm, Helena Malmgren, Anna Norberg, Mikael Sundin, Ann Nordgren, Marianne Farnebo

1291 related Products with: Biallelic mutations in WRAP53 result in dysfunctional telomeres, Cajal bodies and DNA repair, thereby causing Hoyeraal-Hreidarsson syndrome.

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#31387111   2019/08/06 To Up

Haplotype and linkage disequilibrium of TP53-WRAP53 locus in Iranian-Azeri women with breast cancer.

Among the cancer susceptibility genes, TP53 is one of the crucial genes involved in cell cycle regulations and, therefore, it greatly affects breast cancer initiation and progression. In addition, WRAP53-a natural antisense transcript-regulates TP53 transcription and, as a protein, modulates the normal cell cycle, which results in breast cancer susceptibility. In this study, we aimed to analyze a haplotype comprising four SNPs, including rs1042522, rs17878362, rs2287499, and rs2287498, which are located at 5' regions of the TP53 and WRAP53 genes, in 118 patients and 110 healthy controls of the Iranian-Azeri population. In silico studies were conducted using the SIFT, Polyphen2, Fanthmm, RNAsnp, and SNP&GO online servers. Linkage disequilibrium (LD) and D' for each combination of the markers were calculated via the Haploview program. Our results showed that the GA1CC haplotype was the most frequent in the studied population. Additionally, no significant LD between any pairwise haplotypes was observed. The GA1CC and CA2GC haplotypes were significantly associated with breast cancer susceptibility. Moreover, the in silico analysis revealed the negative effects of rs2287499 and rs1042522 on WRAP53 and P53, respectively. In conclusion, the CA1GC haplotype was strongly identified as a breast cancer risk factor, and the GA1CC haplotype was assumed to be a protective factor against breast cancer risk. Hence, these markers may potentially be used as molecular prognostic and predictive biomarkers for breast cancer.
Nasser Pouladi, Sepehr Abdolahi, Davoud Farajzadeh, Mohammad Ali Hosseinpour Feizi

1628 related Products with: Haplotype and linkage disequilibrium of TP53-WRAP53 locus in Iranian-Azeri women with breast cancer.



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#31361345   2019/07/30 To Up

Therapeutic strategies for targeting telomerase in cancer.

Telomere and telomerase play important roles in abnormal cell proliferation, metastasis, stem cell maintenance, and immortalization in various cancers. Therefore, designing of drugs targeting telomerase and telomere is of great significance. Over the past two decades, considerable knowledge regarding telomere and telomerase has been accumulated, which provides theoretical support for the design of therapeutic strategies such as telomere elongation. Therefore, the development of telomere-based therapies such as nucleoside analogs, non-nucleoside small molecules, antisense technology, ribozymes, and dominant negative human telomerase reverse transcriptase are being prioritized for eradicating a majority of tumors. While the benefits of telomere-based therapies are obvious, there is a need to address the limitations of various therapeutic strategies to improve the possibility of clinical applications. In this study, current knowledge of telomere and telomerase is discussed, and therapeutic strategies based on recent research are reviewed.
Xing Chen, Wen-Jian Tang, Jing Bo Shi, Ming Ming Liu, Xin-Hua Liu

2921 related Products with: Therapeutic strategies for targeting telomerase in cancer.



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#31311806   2019/07/16 To Up

Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells.

Telomerase is expressed in the majority (>85%) of tumors, but has restricted expression in normal tissues. Long-term telomerase inhibition in malignant cells results in progressive telomere shortening and reduction in cell proliferation. Here we report the synthesis and characterization of radiolabeled oligonucleotides that target the RNA subunit of telomerase, hTR, simultaneously inhibiting enzymatic activity and delivering radiation intracellularly. Oligonucleotides complementary (Match) and noncomplementary (Scramble or Mismatch) to hTR were conjugated to diethylenetriaminepentaacetic dianhydride (DTPA), allowing radiolabeling with the Auger electron-emitting radionuclide indium-111 (In). Match oligonucleotides inhibited telomerase activity with high potency, which was not observed with Scramble or Mismatch oligonucleotides. DTPA-conjugation and In-labeling did not change telomerase inhibition. In telomerase-positive cancer cells, unlabeled Match oligonucleotides had no effect on survival, however, In-labeled Match oligonucleotides significantly reduced clonogenic survival and upregulated the DNA damage marker γH2AX. Minimal radiotoxicity and DNA damage was observed in telomerase-negative cells exposed to In-Match oligonucleotides. Match oligonucleotides localized in close proximity to nuclear Cajal bodies in telomerase-positive cells. In comparison with Match oligonucleotides, In-Scramble or In-Mismatch oligonucleotides demonstrated reduced retention and negligible impact on cell survival. This study indicates the therapeutic activity of radiolabeled oligonucleotides that specifically target hTR through potent telomerase inhibition and DNA damage induction in telomerase-expressing cancer cells and paves the way for the development of novel oligonucleotide radiotherapeutics targeting telomerase-positive cancers. SIGNIFICANCE: These findings present a novel radiolabeled oligonucleotide for targeting telomerase-positive cancer cells that exhibits dual activity by simultaneously inhibiting telomerase and promoting radiation-induced genomic DNA damage.
Mark R Jackson, Bas M Bavelaar, Philip A Waghorn, Martin R Gill, Afaf H El-Sagheer, Tom Brown, Madalena Tarsounas, Katherine A Vallis

1736 related Products with: Radiolabeled Oligonucleotides Targeting the RNA Subunit of Telomerase Inhibit Telomerase and Induce DNA Damage in Telomerase-Positive Cancer Cells.

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#31243981   2019/06/22 To Up

Pesticide Exposure Modifies DNA Methylation of Coding Region of , an Antisense Sequence of in a Mexican Population.

The influence of pesticide exposure in alteration of DNA methylation patterns of specific genes is still limited, specifically in natural antisense transcripts (NAT), such as the gene. The aim of this study was to determine the methylation of the gene in mestizo and indigenous populations as well as its relationship with internal (age, sex, and body mass index) and external factors (pesticide exposure and micronutrient intake). A cross-sectional study was conducted including 91 mestizo individuals without occupational exposure to pesticides, 164 mestizo urban sprayers and 189 indigenous persons without occupational exposure to pesticides. Acute pesticide exposure was evaluated by measurement of urinary dialkylphosphate (DAP) concentration by gas chromatograph coupled to a mass spectrometer. Anthropometric characteristics, unhealthy habits, and chronic pesticide exposure were assessed using a structured questionnaire. The frequency of macro- and micronutrient intake was determined using SNUT software. DNA methylation of the gene was determined by pyrosequencing of bisulfite-modified DNA. The mestizo sprayers group had the higher values of %5mC. In addition, this group had the most DAP urinary concentration with respect to the indigenous and reference groups. Bivariate analysis showed an association between %5mC of the gene with micronutrient intake and pesticide exposure in mestizo sprayers, whereas changes in %5mC of the gene was associated with body mass index in the indigenous group. These data suggest that the %5mC of the gene can be influenced by pesticide exposure and ethnicity in the study population, and changes in the gene might cause an important cell process disturbance.
Diana M Paredes-Céspedes, José F Herrera-Moreno, Yael Y Bernal-Hernández, Irma M Medina-Díaz, Ana M Salazar, Patricia Ostrosky-Wegman, Briscia S Barrón-Vivanco, Aurora E Rojas-García

2059 related Products with: Pesticide Exposure Modifies DNA Methylation of Coding Region of , an Antisense Sequence of in a Mexican Population.

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