Non-telomeric activities of telomerase

Recent results suggest that telomerase is involved in many more cellular processes than merely telomere elongation. These include telomere-independent anti-apoptotic, cytoprotective and pro-proliferative effects of telomerase or protection of mitochondrial DNA against oxidative stress. Telomerase also participates in DNA repair and its essential subunits, hTR and hTERT, are able to modulate independently the cell's response to DNA damage. Recent high throughput analyses of gene expression showed that hTERT expression modulates expression of about 300 genes, including genes involved in the regulation of cell cycle progression, proliferation and differentiation. Besides the well-known telomerase catalytic activity of RNA-dependent DNA polymerase, its RNA-dependent RNA polymerase activity was recently described in association with the RNA subunit of mitochondrial RNA processing endoribonuclease, thus suggesting involvement of telomerase in RNA interference processes. These recent discoveries open novel possibilities and entirely unexpected research perspectives, branching off from the mainstream telomere and telomerase research.     

端粒酶研究的若干进展

端粒酶是一种ＲＮＡ依赖的ＤＮＡ聚合酶。它的生物学功能在于以自身的ＲＮＡ为模板,合成端粒序列,解决了线性染色体的末端复制问题,维持了染色体的稳定性。本文介绍一些新进展：如端粒酶蛋白的ｃＤＮＡ已被克隆;端粒酶活性检测中出现误差的可能原因;端粒酶活性的调控因子ＴＲＦ１及新发现的ＴＲＦ２;端粒酶活性同肿瘤诊断及预后间的关系;端粒酶的激活同肿瘤发生间的关系;反义核酸抑制端粒酶活性的可能性及其可能发生的问题等。     

Utilization of ribonucleotides and RNA primers by Tetrahymena telomerase.

Telomerase is a ribonucleoprotein (RNP) DNA polymerase involved in telomere synthesis. A short sequence within the telomerase RNA component provides a template for de novo addition of the G-rich strand of a telomeric simple sequence repeat onto chromosome termini. In vitro, telomerase can elongate single-stranded DNA primers processively: one primer can be extended by multiple rounds of template copying before product dissociation. Telomerase will incorporate dNTPs or ddNTPs and will elongate any G-rich, single-stranded primer DNA. In this report, we show that Tetrahymena telomerase was able to incorporate a ribonucleotide, rGTP, into product polynucleotide. Synthesis of the product [d(TT)r(GGGG)]n was processive, suggesting that the chimeric product remained associated with the enzyme both at the active site and at a second, previously characterized, template-independent product binding site. As predicted by this finding, RNA-containing oligonucleotides served as primers for elongation. More than 3 nt of RNA at a primer 3' end decreased the quantity of product synthesis but increased the affinity of the primer for telomerase. Thus, RNA-containing primers were effective as competitive inhibitors of DNA primer elongation by telomerase. These results support the possible evolutionary origin of telomerase as an RNA-dependent RNA polymerase.     

Telomerase redefined: integrated regulation of hTR and hTERT for telomere maintenance and telomerase activity

Telomerase activity is dependent on the expression of 2 main core component genes, hTERT, which encodes the catalytic component and hTR (also called TERC), which encodes the RNA component. The correlation between telomerase activity and carcinogenesis has made this molecule of great interest in cancer research, however in order to fully understand the regulation of telomerase the mechanisms controlling both telomerase genes need to be studied. Some of these mechanisms of regulation have begun to emerge, however many more remain to be deciphered. For many years hTERT has been regarded as the limiting component of telomerase and much of the research in this field has focussed on its regulation, however it was clear from an early stage that hTR expression was also tightly regulated in normal cells and disease. More recently evidence from biochemistry, promoter studies and mouse models has been steadily increasing for a role for hTR as a limiting and essential component for telomerase activity and telomere maintenance. Perhaps the time has come to redefine our view of telomerase regulation. Knowledge of the mechanisms controlling both telomerase genes in normal systems and cancer may aid our understanding of the role of telomerase in carcinogenesis or highlight potential areas for therapeutic intervention. Here we review the essential requirement of hTR for telomere maintenance and telomerase activity in normal tissues and disease and focus on recent advances in our understanding of hTR regulation in relation to hTERT.     

应用mTR-/-鼠模型系统研究肿瘤发生机制的进展

端粒酶是真核细胞体内的一种核糖核酸蛋白质复合体,是一种特殊的DNA聚合酶,具有延伸DNA末端的功能,能够维持端粒长度和功能,TERT具有反转录酶活性。在大多数体细胞和原代细胞中,端粒酶活性很低,通常检测不到,但在肿瘤细胞中,端粒酶则被广泛激活,因此认为端粒酶与肿瘤的发生具有密切的关系,本介绍了应用端粒酶阴性鼠研究端粒酶与G链悬垂和P53在肿瘤的发生过程中的相互关系。     

Downregulation of telomerase in rat during the aging process.

Telomerase is an RNA-dependent DNA polymerase that maintains the tandem arrays of telomeric repeats at the eukaryotic chromosome ends. Because of its ability to replenish lost telomeric sequences, telomerase is thought to be required for cell proliferation. At present, very little information on the role of telomerase in aging is available. In the present study, we tested the telomerase activity of Fischer 344 rat testis and liver at 6, 12, 18 and 24 months of age. As the testis is an androgen-dependent tissue, we also investigated the changes of testosterone and mRNA levels of androgen receptor in this tissue. Our results show that the telomerase activity of Fischer 344 rat testis significantly reduced at 24 months of age compared to 6 months of age, and that the mRNA level of telomerase protein component 1 (TLP-1) show a corresponding decrease with the telomerase activity. Interestingly, this down-regulation was not observed in the liver. The testosterone level in testis increased until 18 months of age, but reduced by 50% at 24 months of age. Our conclusions are that the telomerase activity is age-dependent and its change is a tissue-specific phenomenon.