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Telomerase Regulation: a Key to Inhibition? (Review) INTERNATIONAL JOURNAL OF ONCOLOGY 43: 1351-1356, 2013 Telomerase regulation: A key to inhibition? (Review) DIEGO L. MENGUAL GÓMEZ, HERNÁN G. FARINA and DANIEL E. GÓMEZ Laboratory of Molecular Oncology, Science and Technology Department, National University of Quilmes, Buenos Aires, Argentina Received May 27, 2013; Accepted July 5, 2013 DOI: 10.3892/ijo.2013.2104 Abstract. Telomerase has been recognized as a common factor of a guanine-rich sequences. In humans, telomeres are in most tumor cells, and in turn a distinctive feature with respect comprised of a repetitive TTAGGG sequence with a 3' G-rich to non-malignant cells. This feature has made telomerase a single-stranded overhang (1,2). The ends of telomeres form a promising target for cancer therapy. Telomerase studies revealed lariat-like structure called t-loop (3), which is postulated to that it is a multi-subunit complex possessing different levels of be formed by strand invasion of the 3' single strand overhang regulation, including control of expression, phosphorylation into the preceding double stranded telomeric DNA that is then state, assembly and transportation to sites of activity. Thus, we stabilized by telomeric proteins (4). A six-protein complex emphasize that targeting telomerase expression or activity is not known as ‘shelterin’ has remarkable specificity for telomeres the only way to shorten telomeres, induce cell senescence and and some members of the complex specifically binds to apoptosis. Therefore, there are multiple sites capable of allowing telomeric DNA. These proteins are: telomere repeat binding the modulation of its enzymatic activity. In the development of factor 1 (TRF1), telomere repeat binding factor 2 (TRF2), strategies based on the regulation of telomerase activity the repressor/activator protein 1 (RAP1), protection of telomeres 1 understanding of the mechanisms regulating their subunits (POT1), TRF1 interacting nuclear factor 2 (TIN2), and TPP1 is essential. Based on this, in this review we summarize the [also known POT1 and TIN2 organizing protein (5-8)]. The current state of knowledge of some regulatory mechanisms of functions of shelterin protein components are to maintain the components of the telomerase complex, and hypothetize telomere length, promote t-loop formation, recruit telomerase their potential therapeutic application against cancer. to telomeric ends, and protect the ends of chromosomes from being recognized as DNA damage (5,8,9). The cell replication apparatus is not able to provide for complete replication of Contents chromosome ends; also, telomeres are subject to the action of nucleases and other deleterious factors. As a result, telomeres 1. Telomere structure and function shorten during each cell division. In most organisms the main 2. Telomerase holoenzyme mechanism of telomere length maintenance is completion 3. TERT regulation of DNA telomere repeats by telomerase (10). In other cases 4. Nuclear transport of TR there is a non-telomerase mechanism, known as alternative 5. Assembly of telomerase complex lengthening of telomeres (ALT) which involves the use of a 6. Regulation of telomerase by telomere binding DNA template (11). Most cancer cells have a chromosome end 7. Conclusion/summary renewal mechanism involving the telomerase complex, which utilizes its integral RNA molecule as a template for reverse transcription of new telomeric DNA. In normal, healthy cells 1. Telomere structure and function telomerase activity is mostly limited to embryonic cells, adult germline cells, and stem cells but is virtually absent Telomeres are regions of repetitive nucleotide sequences in somatic cells (12) while it is rather common in the vast at each end of chromosomes, this region is a repetition majority of cancer cells (13,14), providing important targets for detection and treatment (Fig. 1). 2. Telomerase holoenzyme Correspondence to: Dr Daniel Gómez, Laboratory of Molecular The telomerase is a specific reverse transcriptase responsible Oncology, Science and Technology Department, National University of Quilmes, Roque Saenz Peña 352 (1876), Buenos Aires, Argentina for the maintenance of telomere length in most mammals; this E-mail: [email protected] enzyme was initially identified in ciliates (15). The human telomerase is comprised of two main subunits, the RNA Key words: telomerase, telomeres, cancer, telomerase activity template and the catalytic enzyme (16). The telomerase RNA regulation template (hTR or hTERC) contains a complementary sequence to the human telomere that serves as the base for replication of short repetitive telomere sequences d(TTAGGG) (17). The 1352 GÓMEZ et al: TELOMERASE REGULATION responsible for at least partially maintaining telomere length homeostasis in germ cells and other stem-like cells in which telomerase is active (25). Thus, it would be possible that other mechanisms regulating telomerase recruitment or proces- sivity exist depending on whether cells are at equilibrium conditions versus non-equilibrium conditions. 3. TERT regulation Intensive studies of telomerase functioning in human cells gave new perspectives on the mechanism of senescence, stem cells and cancer therapy. The studies show that numerous enzymes are required for telomerase functioning that facilitate new approaches for inhibiting telomerase in cancer treatment. Probably there are still numerous unrevealed Figure 1. Telomere lengths vs cell divisions. The cells that have a constitutive telomerase activity (embryonic and pluripotent stem cells) may completely proteins that contribute to regulation of such a dynamic maintain telomere lengths. Stem cells transiently express telomerase or express complex that still are to be discovered. As already reported, moderate amounts of telomerase maintaining partially telomeric length, with TERT splice variants may be expressed in normal, pre-crisis increased age and cell divisions, telomeres continue to shorten in these cells. and alternative lengthening of telomeres cells (ALT) that lack Normal somatic cells that do not express telomerase have their telomeres shorten with each cell division. Cancer cells which reactivate or upregulate detectable telomerase activity (26-28). Thus, transcriptional telomerase fully maintain telomeres but generally at reduced lengths. This control of TERT is supposed to play a crucial role in the feature has made telomerase a promising target for cancer therapy. complex regulation of telomerase activity. Post-translational regulation of telomerase activity can occur via reversible phosphorylation of TERT catalytic subunit at specific serine/ threonine or tyrosine residues. Due to multiple kinase and extension of telomeres is completed through the catalytic phosphatase activators and inhibitors the telomerase phos- component, its reverse transcriptase (hTERT) (18). Along phorylation status may affect its structure, localization and with these two main components are additional telomere/ enzyme activity (29). Numerous non-specific phosphoryla- telomerase associated proteins. These accessory proteins tion sites within TERT protein are postulated but only a few regulate telomerase biogenesis, their subcellular localization, of them appear to be the key residues, and their phosphoryla- and function in vivo. Formation of the functional holoen- tion influences telomerase activity (activation and inhibition) zyme complex requires associated proteins including the box (30). Specific phosphorylation site at TERT is present at the H/ACA small nucleolar RNA proteins: dyskerin, nucleolar proline rich region (29). It was revealed that the contribution protein 10 (NOP10), non-histone protein 2 (NHP2), and of c-Abl tyrosine kinase to TERT phosphorylation at specific glycine-arginine rich 1 (GAR1) (19). Other proteins involved tyrosine residues led to decreased telomerase activity. It was in the telomerase complex are pontin/reptin and telomerase shown that overexpression of c-Abl inhibited cell growth by Cajal body protein 1 (TCAB1) (20). Pontin and reptin are two causing cell cycle arrest (30). Because of the role of c-Abl ATPases, which interact with TERT in the S phase of the cell in stress response to DNA damage, exposure of cells to cycle, showing a TERT dependent regulation of cell cycle. ionizing radiation led to a significant increase in TERT phos- Pontin and reptin interact with TERT, suggesting that pontin phorylation by c-Abl. It was also demonstrated that c-Abl and reptin also serve to assemble or remodel a telomerase phosphorylated TERT is leading to inhibition of telomerase complex containing TERT. This process may occur in a step- activity and decrease in telomere length (31) suggesting a wise fashion in which pontin and reptin facilitate assembly direct association between c-Abl and TERT. In conclusion, of TERT with a TR-dyskerin RNP, or remodel this maturing TERT expression is regulated at both, transcriptional and telomerase complex (21). Finally the factor TCAB1 regulates post-transcriptional levels, with the alternative splicing of the subcellular location of telomerase (22). TERT also involved in the control of telomerase activity. Telomerase levels are regulated at every step of protein However, contradictive reports concern the correlation of and RNA processing, as well as at the level of complex telomere length with telomerase activity or TERT expression assembly and subcellular localization (23). Telomerase in different cells which might confirm the tissue-specificity activity at the telomere is also regulated at the level of telom- of
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