THE ROLE OF TELOMERIC ACTIVITY AND TELOMERASES IN AGING WITH NEOPLASIC CHANGES

Year 2020, Issue: 045, 267 - 282, 31.12.2020

Esra Bilici

Abstract

The effect of telomeres on aging and cancer is very important. Telomere is a necessary structure for the continuous preliferation of human cells and is vital for most cancer cells. Telomeric structures located at the ends of the chromosomes consist of TTAGGG repeat units. Telomere terminal transferase is the enzyme responsible for telomere synthesis. It is also a large enzyme complex. Reverse transcriptase provides activation by strengthening the wearing parts after high telomere loss. In addition, it has been suggested that there are cancer cells that do not have telomerase activity but are able to extend the length of telomeres. In the timeframe of cellular division, telomerase enzyme can repair these errors if telomere sequences are lost. In cases where it is not repaired, the protection of these areas is eliminated. Thus, shortening occurs at the ends of the chromosomes. It has been researched by scientists that this shortening causes cellular aging. Reverse transcriptase enzyme has been reported to cause tumorigenic transformation of human epithelial cells and fibroblasts by cooperating with a number of oncogenes and suppressing several tumor suppressor genes. Studies on telomere shortening prove that this enzyme can have a strong effect in the treatment of cancer and is an important development for many patients who are expecting hope. Studies conducted in recent years are among the ideas that the structures and telomerase activity of telomere regions play an active role in cell aging and cancer formation. In the light of all these data, there is not a complete solution of aging, but studies are still ongoing today and major steps have been taken regarding cancer treatment. In this review, the definition of telomeres, their purpose, measurement methods and current studies are given.

Keywords

Telomere, Telomerase, Cancer, Aging

References

• [1] Atlı, K., Bozcuk, A.N., (2002), Telomerler ve hücresel yaşlanma, Geriatri, 5, 111-4.
• [2] Turner, K.J., Vasu, V., Griffin, D.K., (2019), Telomere Biology and Human Phenotype, Cells, doi.org/10.3390/cells8010073. [3] Blackburn, E.H., (1991), Structure and function of telomeres, Nature, 350, 569–573.
• [4] de Lange, T., (2005), Shelterin: the protein complex that shapes and safeguards human telomeres, Genes Dev., 19, 2100–2110.
• [5] Watson, J.D., (1972), Origin of concatemeric T7 DNA, Nat. N. Biol., 239, 197–201.
• [6] Harley, C.B., Futcher, A.B., Greider, C.W., (1990), Telomeres shorten during ageing of human fibroblasts, Nature, 345, 458–460.
• [7] López-Otín, C., Blasco, M.A., Partridge, L., Serrano, M., Kroemer, G., (2013), The hallmarks of aging, Cell, doi.org/10.1016/j.cell.2013.05.039.
• [8] d’Adda di Fagagna, F., (2003), A DNA damage checkpoint response ın telomere-ınitiated senescence, Nature, 426, 194–198.
• [9] Blasco, M.A., (2007), Telomere length, stem cells and aging, Nat. Chem. Biol., doi.org/10.1038/nchembio.2007.38.
• [10] Blackburn, E.H., (1992), Telomerases, Annu. Rev. Biochem, 61,113-129.
• [11] Başaran, A., (2000), Telomer-telomeraz ve hücre yaşlanması, Denizli Tıbbi Biyoloji Kongre Özet Kitabı, 40-41.
• [12] de Lange, T., Shiue, L., Myers, R.M., Cox, D.R., Naylor, S.L., Killery, A.M., Varmus, H.E., (1990), Structure and variability of human chromosome ends, Mol Cell Biol., 10(2), 518-527.
• [13] Slijepcevic, P., (1998), Telomere length regulation-a view from the ındividual chromosome perspective, Experimental Cell Research, 244, 268-74.
• [14] Shay, J.W., Wright, W.E., (2019), Telomeres And Telomerase: three decades of progress, Nature Reviews Genetics, 20, 299–309.
• [15] Sun, D., Lopez-Guajardo, C.C., Quada, J., (1999), Regulation of catalytic activity and processivity of human telomerase, Biochemistry, 38, 4037-44.
• [16] Shay, J.W., Zou, Y., Hiyama, E., Wright, W.E., (2001), Telomerase and cancer, Hum. Mol. Genet., 10, 677-685.
• [17] Grander, M.P., Wright, W.E., Shay, J.W., (2002), Telomerase in cancer and aging. Crit. Rev. Oncol. Hematol., 41, 29-40.
• [18] Hahn, W.C., (2005), Telomere and telomerase dynamics in human cells. Curr. Mol. Med., 5, 227-31.
• [19] Prescott, J.C., Blackburn, E.H., (1999), Telomerase: Dr Jekyll or Mr. Hyde, Curr. Opin, Genetics and Development, 9, 368-373.
• [20] Roake, C.M., Artandi, S.E., (2020), Regulation of human telomerase in homeostasis and disease. Nature Reviews Molecular Cell Biology, 551, 6.
• [21] Kurt, N., (2014), Köpeklerde telomeraz mRNA (dogtert) ekspresyonunun belirlenmesi, Adnan Menderes Üniversitesi Sağlık Bilimleri Enstitüsü Yüksek Lisans Tezi (Basılmış).
• [22] Angelopoulou, K., Zavlaris, M., Papaioannou, N., Vlemmas, I., (2008), canis familiaris telomerase reverse transcriptase undergoes alternative splicing, Mamm Genome, 19(9), 647-53.
• [23] Sieverling, L., Hong, C., Koser, S., Ginsbach, P., Kleinheinz, K., Hutter, B., Braun, D., Cortés-Ciriano, I., Xi, R., Kabbe, R., Park, P., Eils, R., Schlesner, M., (2020), Genomic footprints of activated telomere maintenance mechanisms in cancer, Nature Communications volume 11, 733.
• [24] Edo, M.D., Andrés, V., (2005), Aging telomeres and atherosclerosis, Cardiovasc Res., 1,66(2), 213-21.
• [25] Bajaj, S., Kumar, M.S., Peters, G.J., Mayur, Y.C., (2020), Targeting telomerase for its advent in cancer therapeutics, doi: 10.1002/med.21674.
• [26] Nugent, C.I., Lundblad, V., (1998), The telomerase reverse transcriptase. components and regülation, Genes and Developments, 12, 1073-1085.
• [27] Qulton, R., Harrington, L., (2000), Telomeres telomerase and cancer life on the edge of genomic stability, Curr. Opin Oncol., 12, 74-81.
• [28] Kevser, P.Ö., (2000), Telomeraz. Hacettepe Tıp Dergisi, 31(2), 158-68.
• [29] Zakian, V.A., (1995), Telomeres beginning to understand the end. Science, 270, 1601-6.
• [30] Liu, D., O’connor, M.S., Quin, J., Songyang, Z., (2004), Telosome: mammalian telomere-associated complex formed by multiple telomeric proteins, J. Biol. Chem., 279, 51338-51342.
• [31] Cong, Y.S., Woodring, E., Shay, J.W., (2002), Human telomerase and its regulation, Microbiol. Mol. Biol. Rev., 66, 407-425.
• [32] Horikawa, I., Barrette, J.C., (2003), Transcriptional regulation of the telomerase hTERT gene as a target for cellular and viral oncogenic mechanisms, Carcinogenesis, 24(7), 1167-76.
• [33] Kim, N.W., Piatyszek, M.A., Prowse, K.R., (1994), Specific association of human telomerase activity with immortal cells and cancer, Science, 266, 2011-15.
• [34] Chan, S.R.W.L., Blackburn, E.H., (2004), Telomeres and telomerase, Phil.Trans. R. Soc. Lond, 359, 109-121.
• [35] Geyikli, İ., Bayıl, S., Çiçek, H., (2007), Yaşlanma ve telomeraz, Türk Klin Biyok Der., 5(3), 111- 115.
• [36] McKevitt, T.P., Nasir, L., Devlin, P., Argyle, D.J., (2002), Telomere lengths in dogs decrease with increasing donor age, J Nutr. Jun, 132(6 Suppl 2), 1604S-6S.
• [37] Gelmini, S., Caldini, A., Becherini, L, Capaccioli, S., Pazzagli, M., Orlando, C., (1998), Rapid quantitative nonisotopic assay for telomerase activity in human tumors, Clin Chem., 44(10), 2133 8.
• [38] Hirose, M., Hashımoto, J.A., Tahara, H., Ide, T., Yoshimura, T., (1998), New method to measure telomerase activity by transcription-mediated amplification and hybridization protection assay, Clinical Chemeistry, 44(12), 2446-2452.
• [39] Aldous, W.K., Grabill, N.R., (1997), A fluorescent method for detection of telomerase activity, Diagnostic Molecular Pathology, 6(2), 102-110.
• [40] Zavlaris, M., Angelopoulou, K., Vlemmas, I., Papaioannou, N., (2009), Telomerase reverse transcriptase (TERT) expression in canine mammary tissues: a specific marker for malignancy, AnticancerRes., 29(1), 319-25.
• [41] Liu, D.Y., Peng, Z.H., Qiu, G.Q., Zhou, C.Z., (2003), Expression of telomerase activity and oxidative stres in human hepatocellular carcinoma with cirrhosis, World J Gastroentero, 9(8), 1859-1862.
• [42] Dikmen, G., Doğan, P., (2003), Telomeraz ve kanser, Turk Klin Tip Bilim, 23, 334-341.
• [43] Greenberg, R.A., (2005), Telomeres crisis and cancer, Curr. Mol. Med., 5, 213-218.
• [44] Kavaler, E., Landman, J., Chang, Y., (1998), Detecting human bladder carcinoma cells in voided urine samples by assaying for the presence of telomerase activity, Cancer, 82,708-14 11.
• [45] Brian, C.S., Liu, K., Loughlin, R., (2000), Telomerase in human bladder cancer, Urologic Clinics of North America, 27(1), 115-23.
• [46] Shay, J.W., (1998), Telomerase in cancer: diacnostic, prognostic and therapeutic implications, Cancer J Sci Am, 4, 26-34.
• [47] Nault, J.C., Ningarhari, M., Rebouissou, S., Zucman, R.J., (2019), The role of telomeres and telomerase in cirrhosis and liver cancer, Nature Reviews Gastroenterology & Hepatology, 16, 544–558.
• [48] Güneş, Ç., Wezel, F., Southgate, J., Bolenz, C., (2018), Implications of TERT promoter mutations and telomerase activity in urothelial carcinogenesis, Nature Reviews Urology, 15, 386–393.
• [49] Graham, M.K., Meeker, A., (2017), Telomeres and telomerase in prostate cancer development and therapy, Nature Reviews Urology, 14, 607–619.
• [50] Lin, Y., Seger, N., Chen, Y., Hesla, A.C., Wejde, J., Ghaderi, M., Tsagkozis, P., Larsson, O., Haglund, F., (2018), hTERT promoter mutations in chondrosarcomas associate with progression and disease-related mortality, Modern Pathology, 31, 1834–1841.
• [51] Stögbauer, L., Stummer, W., Senner, V., Brokinkel, B., (2020), Telomerase activity, TERT expression, hTERT promoter alterations, and alternative lengthening of the telomeres (ALT) in meningiomas - a systematic review, Neurosurg Rev., doi: 10.1007/s10143-019-01087-3.
• [52] Smith, J.S., Johnson, F.B., (2010), Isolation of G-Quadruplex DNA using nmm-sepharose affinity chromatography ın baumann p. (eds), G-Quadruplex DNA: methods and protocols, Methods in Molecular Biology, 608 DOI 10. 1007/978-1-59745-363-9_13.
• [53] Neidle, S., (2017), Quadruplex nucleic acids as targets for anticancer therapeutics, Nat. Rev. Chem., 1, 0041.
• [54] Hansel-Hertsch, R., Di Antonio, M., Balasubramanian, S., (2017), DNA G-quadruplexes in the human genome: detection, functions and therapeutic potential. Nat. Rev. Mol. Cell Biol., 18, 279–284.
• [55] Wu, Y.L., (2017), G-quadruplex organic frameworks, Nat. Chem., 9, 466–472.
• [56] Yatsunyk, L.A., Mendoza, O., Mergny, J.L., (2014), “Nano-oddities”: unusual nucleic acid assemblies for DNA-based nanostructures and nanodevices, Acc. Chem. Res., 2014, 47, 6, 1836-1844.
• [57] Davis, J.T., (2004), G-quartets 40 years later: from 5’-GMP to molecular biology and supramolecular chemistry, Angew. Chem. Int. Ed., 43, 668–698.
• [58] Neidle, S., Parkinson, G., (2002), Telomere maintenance as a target for anticancer drug discovery, Nat Rev Drug Discov., 1(5),383-93. [59] Qin, Y., Hurley, L.H., (2008), Structures, folding patterns, and functions of intramolecular DNA G-quadruplexes found in eukaryotic promoter regions, Biochimie, 90, 1149–1171.
• [60] Balasubramanian, S., Hurley, L.H., Neidle, S., (2011), Targeting G-quadruplexes in gene promoters: a novel anticancer strategy, Nat. Rev. Drug. Discov., 10, 261–275.
• [61] Moyzis, R.K., (1988), A highly conserved repetitive DNA sequence, (TTAGGG)n, present at the telomeres of human chromosomes, Proc. Natl Acad. Sci., 85, 6622–6626.
• [62] Wright, W.E., Tesmer, V.M., Huffman, K.E., Levene, S.D., Shay, J.W., (1997), Normal human chromosomes have long G-rich telomeric overhangs at one end. Genes Dev., 11, 2801–2809.
• [63] Bodnar, A.G., (1998), Extension of life-span by introduction of telomerase into normal human cells, Science, 279, 349–352.
• [64] Hurley, L.H., (2002), DNA and its associated processes as targets for cancer therapy, Nat. Rev. Cancer, 2, 188–200.
• [65] Greider, C.W., Blackburn, E.H., (1985), Identification of a specific telomere terminal transferase activity in Tetrahymena extracts, Cell, 43, 405–413.
• [66] Kim, N.W., Piatyszek, M.A., Prowse, K.R., Harley, C.B., West, M.D., Ho, P.L., Coviello, G.M., Wright, W.E., Weinrich, S.L., Shay, J.W., (1994), Specific association of human telomerase activity with immortal cells and cancer, Science, 266(5193),2011-5.
• [67] Phan, A.T., (2010), Human telomeric G-quadruplex: structures of DNA and RNA sequences, Febs. J., 277, 1107–1117.
• [68] Lin, C., Yang, D., (2017), İn telomeres and telomerase: methods and protocols (ed. Songyang, Z.) 171–196.
• [69] Zahler, A.M., Williamson, J.R., Cech, T.R., Prescott, D.M, (1991), Inhibition of telomerase by G-quartet DNA structures, Nature, 350, 718–720.
• [70] Sfeir, A., de Lange, T.. (2012), Removal of shelterin reveals the telomere end-protection problem, Science, 336, 593–597.
• [71] Rizzo, A., (2009), Stabilization of quadruplex DNA perturbs telomere replication leading to the activation of an ATR-dependent ATM signaling pathway, Nucleic Acids Res., 37, 5353–5364.
• [72] Liu, W., Zhong, Y.F., Liu, L.Y., Shen, C.T., Zeng, W., Wang, F., Yang, D., Mao, Z.W., (2018), Solution structures of multiple g-quadruplex complexes induced by a platinum(ıı)-based tripod reveal dynamic binding, Nature Communications, 9, 3496.
• [73] Martinez, P., Blasco, M.A., (2018), Heart-breaking telomeres. Circ. Res., 123, 787–802. [74] Frees, S., Menendez, C., Crum, M., Bagga, P.S., (2014), Qgrs-conserve: A computational method for discovering evolutionarily conserved g-quadruplex motifs, Hum. Genom, 8, 8. [75] Zhu, Y., Liu, X., Ding, X., Wang, F., Geng, X., (2019), Telomere and its role in the aging pathways: telomere shortening, cell senescence and mitochondria dysfunction, Biogerontology, doi: 10.1007/s10522-018-9769-1.
• [76] Wattis, J.A.D., Qi, Q., Byrne, H.M., (2020), Mathematical modelling of telomere length dynamics, J Math Biol., doi: 10.1007/s00285-019-01448-y.
• [77] Wright, W.E., Piatyszek, M.A., Rainey, W.E., Byrd, W., Shay, J.W., (1996), Telomerase activity in human germline and embryonic tissues and cells, Dev. Genet., 18, 173–179.
• [78] Jolivet, P., Serhal, K., Graf, M., Eberhard, S., Xu, Z., Luke, B., Teixeia, M.T., (2019), A Subtelomeric region affects telomerase-negative replicative senescence ın saccharomyces cerevisiae, Scientific Reports, 9, 1845.
• [79] Hanahan, D., Weinberg, R.A., (2011), Hallmarks of cancer: the next generation, Cell, 144, 646–74.
• [80] Palm, W., de Lange, T., (2008), How shelterin protects mammalian telomeres, Annu Rev Genet., 42, 301-34. [81] Nandakumar, J., Cech, T.R., (2013), Finding the end: recruitment of telomerase to telomeres, Nat Rev Mol Cell Biol., 14(2),69-82.
• [82] McHugh, D., Gil, J., (2018), Senescence and aging: causes, consequences, and therapeutic avenues, doi: 10.1083/jcb.201708092.
• [83] Hayflick, L., Moorhead, P.S., (1961), The serial cultivation of human telomerase activity diploid cell strains, Exp. Cell Res., 25, 585-621.
• [84] Hayflict L, 1991. Aging Under Glass. Mutation Research. 256: 69-80.
• [85] Klug, W.S., (2000), Cummings M. R, Concept of Genetics, Chapter 12, 340-341. [86] de Magalhães, J.P., (2013), How ageing processes influence cancer, Nat Rev Cancer, 13(5), 357-65. [87] Collado, M., Serrano, M., (2010), Senescence in tumours: evidence from mice and humans, Nat Rev Cancer, 10(1),51-7.
• [88] Kang, T.W., Yevsa, T., Woller, N., Hoenicke, L., Wuestefeld, T., Dauch, D., Hohmeyer, A., Gereke, M., Rudalska, R., Potapova, A., Iken, M., Vucur, M., Weiss, S., Heikenwalder, M., Khan, S., Gil, J., Bruder, D., Manns, M., Schirmacher, P., Tacke, F., Ott, M., Luedde, T., Longerich, T., Kubicka, S., Zender, L., (2011), Senescence surveillance of pre-malignant hepatocytes limits liver cancer development, Nature, 479(7374), 547-51.
• [89] Krtolica, A., Parrinello, S., Lockett, S., Desprez, P.Y., Campisi, J., (2001), Senescent fibroblasts promote epithelial cell growth and tumorigenesis: a link between cancer and aging, Proc Natl Acad Sci U S A, 98(21),12072-7.
• [90] Coppé, J.P., Desprez, P.Y., Krtolica, A., Campisi, J., (2010), The senescence-associated secretory phenotype: the dark side of tumor suppression, Annu Rev Pathol., 5, 99-118.
• [91] Baker, D.J., Childs, B.G., Durik, M., Wijers, M.E., Sieben, C.J., Zhong, J., Saltness, R.A., Jeganathan, K.B., Verzosa, G.C., Pezeshki, A., Khazaie, K., Miller, J.D., van Deursen, J.M.,(2016), Naturally occurring p16(Ink4a)-positive cells shorten healthy lifespan, Nature, 530(7589), 184-9.
• [92] Mc Clintock, B., (1941), The stability of broken ends of chromosomes in zea mays, Genetics, 41, 234-82.
• [93] Blasco, M.A., (2005), Telomeres and human disease: aging, cancer and beyond, Nature Reviews Genetics, 6, 611-22.
• [94] Güzelgül, F., Aksoy, K., (2010), Telomeraz enziminin tanı ve tedavide kullanım alanı, Arşiv 16, 69.
• [95] Yıldız, M., Aras, S., Duman, D., (2009), Telomerlerin yaşlanma ve kanser ilişkisindeki rolü, Türk Hijyen ve Deneysel Biyoloji Dergisi, 66 (4), 187-195.
• [96] Liu, J., Wang, L., Wang, Z., Liu, J.P., (2019), Roles of telomere biology in cell senescence, Replicative and Chronological Ageing Cells, 8(1), 54.