Palabras clave
Telómero
Envejecimiento
Homeostasis del Telómero
Tumor
Terapia Genética Telomerase
Telomere
Aging
Telomere Homeostasis
Tumor
Gene Therapy
Cómo citar
Resumen
La telomerasa es una enzima compuesta principalmente por una transcriptasa inversa y una plantilla de ARN que previene el acortamiento crítico de los extremos de los cromosomas. Este documento de revisión no-sistemática presenta y analiza la función biológica de la telomerasa en relación con la longitud de los telómeros, exponiendo su importancia para la homeostasis del contenido de los cromosomas, la capacidad regenerativa de las células madre, la regulación de la función mitocondrial, el desarrollo de tumores y otras patologías, y el envejecimiento prematuro. Se describió además otra vía para el mantenimiento de los la longitud de los telómeros, que también tiene una relación con la carcinogénesis. Se concluye que a pesar de los resultados obtenidos por distintos experimentos en animales que han mostrado opciones de posibles aplicaciones terapéuticas, aún es necesario indagar más acerca de los mecanismos moleculares que encierra la telomerasa.
Citas
D'Souza Y, Chu TW, Autexier C. A translocation-defective telomerase with low levels of activity and processivity stabilizes short telomeres and confers immortalization. Mol Biol Cell. 2013; 24(9): 1469-79. https://doi.org/10.1091/mbc.e12-12-0889
Aubert G, Lansdorp PM. Telomeres and Aging. Physiological Reviews, 2008; 88 (2), 557-579. https://doi.org/10.1152/physrev.00026.2007
John Hopkins Medicine, McKusick-Nathans Institute of Genetic Medicine, National Human Genome Research Institute (NHGRI). Online Mendelian Inheritance in Man (OMIM): An Online Catalog of Human Genes and Genetic Disorders. Fecha de consulta: 7 de febrero de 2016. Fecha de última actualización: 13 de febrero de 2016. Disponible en: http://www.omim.org/entry/187270?search=telomerase&highlight=telomerase
National Human Genome Research Institute (NHGRI). HUGO Gene Nomenclature Comittee. Fecha de consulta: 7 de febrero de 2016. Fecha de última actualización: 13 de febrero de 2016. Disponible en: http://www.genenames.org/cgi-bin/gene_symbol_report?hgnc_id=HGNC:11727
Bernardes de Jesus B, Blasco M. Telomerase at the intersection of cancer and aging. Trends Genet. 2013; 29(9): 513-20. https://doi.org/10.1016/j.tig.2013.06.007
Gocha ARS, Nuovo G, Iwenofu OH, Groden J. Human sarcomas are mosaic for telomerase-dependent and telomerase- independent telomere maintenance mechanisms: Implications for telomere-based therapies. Am J Pathol. American Society for Investigative Pathology; 2013; 182(1): 41-8. Disponible en: https://doi.org/10.1016/j.ajpath.2012.10.001
Calado RT, Young NS. Telomere diseases. N Engl J Med. 2009; 361:2353-2365. https://doi.org/10.1056/NEJMra0903373
Martínez P, Blasco MA. Telomeric and extra-telomeric roles for telomerase and the telomere-binding proteins. Nat Rev Cancer. 2011; 11: 161-176. https://doi.org/10.1038/nrc3025
Beier F, Foronda M, Martínez P, et al. Conditional TRF1 knockout in the hematopoietic compartment leads to bone marrow failure and recapitulates clinical features of Dyskeratosis Congenita. Blood. 2012; 120: 2990-3000. https://doi.org/10.1182/blood-2012-03-418038
Leri A, et al. Ablation of telomerase and telomere loss leads to cardiac dilatation and heart failure associated with p53 upregulation. EMBO J. 2003; 22: 131-139.
https://doi.org/10.1093/emboj/cdg013
Basel-Vanagaite L, et al. Expanding the clinical phenotype of autosomal dominant dyskeratosis congenita caused by TERT mutations. Haematologica. 2008; 93: 943-944. https://doi.org/10.3324/haematol.12317
Armanios M, et al. Short telomeres are sufficient to cause the degenerative defects associated with aging. Am J Hum Genet. 2009; 85: 823-832. https://doi.org/10.1016/j.ajhg.2009.10.028
Hao LY, et al. Short telomeres, even in the presence of telomerase, limit tissue renewal capacity. Cell. 2005; 123:1121-1131. https://doi.org/10.1016/j.cell.2005.11.020
Morrish TA, Greider CW. Short telomeres initiate telomere recombination in primary and tumor cells. PLoS Genet. 2009; 5: e1000357 https://doi.org/10.1371/journal.pgen.1000357
García-Morán GA, Gaitán AA, García-Cardona A, Clavijo-Grimaldi D, et al. Aspectos biomédicos de las fosfolipasas A2 en la especie humana. MedUNAB, 11, 1 (2008).
Sahin E, et al. Telomere dysfunction induces metabolic and mitochondrial compromise. Nature. 2011; 470: 359-365. https://doi.org/10.1038/nature09787
Hu J, Hwang SS, Liesa M, et al: Antitelomerase therapy provokes ALT and mitochondrial adaptive mechanisms in cancer. Cell. 2012, 148: 651-663. https://doi.org/10.1016/j.cell.2011.12.028
Wu KJ, et al. Direct activation of TERT transcription by c-MYC. Nat Genet. 1999; 21: 220-224. https://doi.org/10.1038/6010
Hoffmeyer K, et al. Wnt/beta-catenin signaling regulates telomerase in stem cells and cancer cells. Science. 2012; 336: 1549-1554. https://doi.org/10.1126/science.1218370
Greider CW. Molecular biology. Wnt regulates TERT--putting the horse before the cart. Science. 2012; 336: 1519-1520. https://doi.org/10.1126/science.1223785
Kyo S, Inoue M. Complex regulatory mechanisms of telomerase activity in normal and cancer cells: how can we apply them for cancer therapy? Oncogene. 2002; 21: 688-697. https://doi.org/10.1038/sj.onc.1205163
González-Suárez E, et al. Telomerase-deficient mice with short telomeres are resistant to skin tumorigenesis. Nat Genet. 2000; 26:114-117. https://doi.org/10.1038/79089
Chin L, et al. p53 deficiency rescues the adverse effects of telomere loss and cooperates with telomere dysfunction to accelerate carcinogenesis. Cell. 1999; 97: 527-538. https://doi.org/10.1016/S0092-8674(00)80762-X
Artandi SE, et al. Telomere dysfunction promotes non-reciprocal translocations and epithelial cancers un mice. Nature. 2000; 406: 641-645. https://doi.org/10.1038/35020592
Chang S, et al. Modeling chromosomal instability and epithelial carcinogenesis in the telomerase-deficient mouse. Semin Cancer Biol. 2001; 11: 227-239. https://doi.org/10.1006/scbi.2000.0374
González-Suárez E, et al. Antagonistic effects of telomerase on cancer and aging in K5-mTert transgenic mice. Oncogene. 2005; 24: 2256-2270. https://doi.org/10.1038/sj.onc.1208413
Tomas-Loba A, et al. Telomerase reverse transcriptase delays aging in cancer-resistant mice. Cell. 2008; 135: 609-622. https://doi.org/10.1016/j.cell.2008.09.034
Vera E, et al. Telomerase Reverse Transcriptase synergizes with calorie restriction to increase health span and extend mouse longevity. PLoS ONE. 2013; 8: e53760. https://doi.org/10.1371/journal.pone.0053760
Jaskelioff M, et al. Telomerase reactivation reverse tissue degeneration in aged telomerase-deficient mice. Nature. 2011; 469: 102-106. https://doi.org/10.1038/nature09603
Bernardes de Jesus B, et al. Telomerase gene therapy in adult and old mice delays aging and increases longevity without increasing cancer. EMBO Mol Med. 2012; 4: 1-14." https://doi.org/10.1002/emmm.201200245