Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)

ilustraciones, diagramas,

Autores:: Santos-Gil, Daniel

Tipo de recurso:

Fecha de publicación:: 2023

Institución:: Universidad Nacional de Colombia

Repositorio:: Universidad Nacional de Colombia

Idioma:: spa

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oai_identifier_str	oai:repositorio.unal.edu.co:unal/84852
network_acronym_str	UNACIONAL2
network_name_str	Universidad Nacional de Colombia
repository_id_str
dc.title.spa.fl_str_mv	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)
dc.title.translated.eng.fl_str_mv	Cellular and Molecular Study of the POLR3A Gene Associated with Neonatal Progeroid Syndrome (Wiedemann-Rautenstrauch Syndrome)
title	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)
spellingShingle	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch) 610 - Medicina y salud::616 - Enfermedades 570 - Biología::572 - Bioquímica 570 - Biología::576 - Genética y evolución Medicina molecular Molecular Medicine Síndrome Progeroide Senescencia Celular Envejecimiento Humano RNA Polimerasa III Nucleolo POLR3A RNA-seq Aging
title_short	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)
title_full	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)
title_fullStr	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)
title_full_unstemmed	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)
title_sort	Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)
dc.creator.fl_str_mv	Santos-Gil, Daniel
dc.contributor.advisor.none.fl_str_mv	Arboleda, Gonzalo
dc.contributor.author.none.fl_str_mv	Santos-Gil, Daniel
dc.contributor.researchgroup.spa.fl_str_mv	Muerte Celular Grupo de Neurociencias-Universidad Nacional de Colombia
dc.contributor.orcid.spa.fl_str_mv	Santos-Gil, Daniel [0000-0002-1309-8081]
dc.contributor.cvlac.spa.fl_str_mv	Santos-Gil, Daniel F. [https://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001688007]
dc.subject.ddc.spa.fl_str_mv	610 - Medicina y salud::616 - Enfermedades 570 - Biología::572 - Bioquímica 570 - Biología::576 - Genética y evolución
topic	610 - Medicina y salud::616 - Enfermedades 570 - Biología::572 - Bioquímica 570 - Biología::576 - Genética y evolución Medicina molecular Molecular Medicine Síndrome Progeroide Senescencia Celular Envejecimiento Humano RNA Polimerasa III Nucleolo POLR3A RNA-seq Aging
dc.subject.decs.spa.fl_str_mv	Medicina molecular
dc.subject.decs.eng.fl_str_mv	Molecular Medicine
dc.subject.proposal.spa.fl_str_mv	Síndrome Progeroide Senescencia Celular Envejecimiento Humano RNA Polimerasa III Nucleolo
dc.subject.proposal.eng.fl_str_mv	POLR3A RNA-seq Aging
description	ilustraciones, diagramas,
publishDate	2023
dc.date.accessioned.none.fl_str_mv	2023-10-30T20:53:20Z
dc.date.available.none.fl_str_mv	2023-10-30T20:53:20Z
dc.date.issued.none.fl_str_mv	2023-06-26
dc.type.spa.fl_str_mv	Trabajo de grado - Maestría
dc.type.driver.spa.fl_str_mv	info:eu-repo/semantics/masterThesis
dc.type.version.spa.fl_str_mv	info:eu-repo/semantics/acceptedVersion
dc.type.content.spa.fl_str_mv	Text
dc.type.redcol.spa.fl_str_mv	http://purl.org/redcol/resource_type/TM
status_str	acceptedVersion
dc.identifier.uri.none.fl_str_mv	https://repositorio.unal.edu.co/handle/unal/84852
dc.identifier.instname.spa.fl_str_mv	Universidad Nacional de Colombia
dc.identifier.reponame.spa.fl_str_mv	Repositorio Institucional Universidad Nacional de Colombia
dc.identifier.repourl.spa.fl_str_mv	https://repositorio.unal.edu.co/
url	https://repositorio.unal.edu.co/handle/unal/84852 https://repositorio.unal.edu.co/
identifier_str_mv	Universidad Nacional de Colombia Repositorio Institucional Universidad Nacional de Colombia
dc.language.iso.spa.fl_str_mv	spa
language	spa
dc.relation.references.spa.fl_str_mv	Adams, D. R., & Eng, C. M. (2018). Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. The New England journal of medicine, 379(14), 1353–1362. https://doi.org/10.1056/NEJMra1711801 Allsopp, R. C., Chang, E., Kashefi-Aazam, M., Rogaev, E. I., Piatyszek, M. A., Shay, J. W., & Harley, C. B. (1995). Telomere shortening is associated with cell division in vitro and in vivo. Experimental cell research, 220(1), 194–200. https://doi.org/10.1006/excr.1995.1306 Arboleda, H., Quintero, L., & Yunis, E. (1997). Wiedemann-Rautenstrauch neonatal progeroid syndrome: report of three new patients. Journal of medical genetics, 34(5), 433–437. https://doi.org/10.1136/jmg.34.5.433 Arboleda, G., Morales, L. C., Quintero, L., & Arboleda, H. (2011). Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome): report of three affected sibs. American journal of medical genetics. Part A, 155A(7), 1712–1715. https://doi.org/10.1002/ajmg.a.34019 Arboleda, H., & Arboleda, G. (2005). Follow-up study of Wiedemann-Rautenstrauch syndrome: long-term survival and comparison with Rautenstrauch's patient "G". Birth defects research. Part A, Clinical and molecular teratology, 73(8), 562–568. https://doi.org/10.1002/bdra.20166 Arimbasseri, A. G., & Maraia, R. J. (2016). RNA Polymerase III Advances: Structural and tRNA Functional Views. Trends in biochemical sciences, 41(6), 546–559. https://doi.org/10.1016/j.tibs.2016.03.003 Astle, M. V., Hannan, K. M., Ng, P. Y., Lee, R. S., George, A. J., Hsu, A. K., Haupt, Y., Hannan, R. D., & Pearson, R. B. (2012). AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene, 31(15), 1949–1962. https://doi.org/10.1038/onc.2011.394 Austad, S. N., & Hoffman, J. M. (2018). Is antagonistic pleiotropy ubiquitous in aging biology? Evolution, medicine, and public health, 2018(1), 287–294. https://doi.org/10.1093/emph/eoy033 Azmanov, D. N., Siira, S. J., Chamova, T., Kaprelyan, A., Guergueltcheva, V., Shearwood, A. J., Liu, G., Morar, B., Rackham, O., Bynevelt, M., Grudkova, M., Kamenov, Z., Svechtarov, V., Tournev, I., Kalaydjieva, L., & Filipovska, A. (2016). Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement. Human molecular genetics, 25(19), 4302–4314. https://doi.org/10.1093/hmg/ddw263 Báez-Becerra, C. T., Valencia-Rincón, E., Velásquez-Méndez, K., Ramírez-Suárez, N. J., Guevara, C., Sandoval-Hernandez, A., Arboleda-Bustos, C. E., Olivos-Cisneros, L., Gutiérrez-Ospina, G., Arboleda, H., & Arboleda, G. (2020). Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mechanisms of ageing and development, 192, 111360. https://doi.org/10.1016/j.mad.2020.111360 Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., Moineau, S., Romero, D. A., & Horvath, P. (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science (New York, N.Y.), 315(5819), 1709–1712. https://doi.org/10.1126/science.1138140 Bernard, G., Chouery, E., Putorti, M. L., Tétreault, M., Takanohashi, A., Carosso, G., Clément, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., & Brais, B. (2011). Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. American journal of human genetics, 89(3), 415–423. https://doi.org/10.1016/j.ajhg.2011.07.014 Boulon, S., Westman, B. J., Hutten, S., Boisvert, F. M., & Lamond, A. I. (2010). The nucleolus under stress. Molecular cell, 40(2), 216–227. https://doi.org/10.1016/j.molcel.2010.09.024 Brown W. T. (1992). Progeria: a human-disease model of accelerated aging. The American journal of clinical nutrition, 55(6 Suppl), 1222S–1224S. https://doi.org/10.1093/ajcn/55.6.1222S Burtner, C. R., & Kennedy, B. K. (2010). Progeria syndromes and ageing: what is the connection?. Nature reviews. Molecular cell biology, 11(8), 567–578. https://doi.org/10.1038/nrm2944 Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 328. https://doi.org/10.1038/s41467-017-00322-z Burke, B., & Stewart, C. L. (2002). Life at the edge: the nuclear envelope and human disease. Nature reviews. Molecular cell biology, 3(8), 575–585. https://doi.org/10.1038/nrm879 Campisi J. (1997). The biology of replicative senescence. European journal of cancer (Oxford, England : 1990), 33(5), 703–709. https://doi.org/10.1016/S0959-8049(96)00058-5 Campisi J. (1998). The role of cellular senescence in skin aging. The journal of investigative dermatology. Symposium proceedings, 3(1), 1–5. Campisi J. (2005). Suppressing cancer: the importance of being senescent. Science (New York, N.Y.), 309(5736), 886–887. https://doi.org/10.1126/science.1116801 Campisi, J., & Robert, L. (2014). Cell senescence: role in aging and age-related diseases. Interdisciplinary topics in gerontology, 39, 45–61. https://doi.org/10.1159/000358899 Cao, H., & Hegele, R. A. (2003). LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). Journal of human genetics, 48(5), 271–274. https://doi.org/10.1007/s10038-003-0025-3 Carter, C. S., Sonntag, W. E., Onder, G., & Pahor, M. (2002). Physical performance and longevity in aged rats. The journals of gerontology. Series A, Biological sciences and medical sciences, 57(5), B193–B197. https://doi.org/10.1093/gerona/57.5.b193 Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015). Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nature medicine, 21(12), 1424–1435. https://doi.org/10.1038/nm.4000 Ciganda, M., & Williams, N. (2011). Eukaryotic 5S rRNA biogenesis. Wiley interdisciplinary reviews. RNA, 2(4), 523–533. https://doi.org/10.1002/wrna.74 Clancy, D. J., Gems, D., Hafen, E., Leevers, S. J., & Partridge, L. (2002). Dietary restriction in long-lived dwarf flies. Science (New York, N.Y.), 296(5566), 319. https://doi.org/10.1126/science.1069366 Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99–118. https://doi.org/10.1146/annurev-pathol-121808-102144 Cole, J. R., Wang, Q., Fish, J. A., Chai, B., McGarrell, D. M., Sun, Y., Brown, C. T., Porras-Alfaro, A., Kuske, C. R., & Tiedje, J. M. (2014). Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic acids research, 42(Database issue), D633–D642. Csoka, A. B., English, S. B., Simkevich, C. P., Ginzinger, D. G., Butte, A. J., Schatten, G. P., Rothman, F. G., & Sedivy, J. M. (2004). Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging cell, 3(4), 235–243. https://doi.org/10.1111/j.1474-9728.2004.00105.x Dieci, G., Fiorino, G., Castelnuovo, M., Teichmann, M., & Pagano, A. (2007). The expanding RNA polymerase III transcriptome. Trends in genetics : TIG, 23(12), 614–622. https://doi.org/10.1016/j.tig.2007.09.001 Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America, 92(20), 9363–9367. https://doi.org/10.1073/pnas.92.20.9363 Ellis, J. A., & Shackleton, S. (2011). Nuclear envelope disease and chromatin organization. Biochemical Society transactions, 39(6), 1683–1686. https://doi.org/10.1042/BST20110744 Eriksson, M., Brown, W. T., Gordon, L. B., Glynn, M. W., Singer, J., Scott, L., Erdos, M. R., Robbins, C. M., Moses, T. Y., Berglund, P., Dutra, A., Pak, E., Durkin, S., Csoka, A. B., Boehnke, M., Glover, T. W., & Collins, F. S. (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, 423(6937), 293–298. https://doi.org/10.1038/nature01629 Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., & Santoro, A. (2018). Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nature reviews. Endocrinology, 14(10), 576–590. https://doi.org/10.1038/s41574-018-0059-4 Freund, A., Patil, C. K., & Campisi, J. (2011). p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. The EMBO journal, 30(8), 1536–1548. https://doi.org/10.1038/emboj.2011.69 George, S., Rochford, J. J., Wolfrum, C., Gray, S. L., Schinner, S., Wilson, J. C., Soos, M. A., Murgatroyd, P. R., Williams, R. M., Acerini, C. L., Dunger, D. B., Barford, D., Umpleby, A. M., Wareham, N. J., Davies, H. A., Schafer, A. J., Stoffel, M., O'Rahilly, S., & Barroso, I. (2004). A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science (New York, N.Y.), 304(5675), 1325–1328. https://doi.org/10.1126/science.1096706 Gingold, H., Tehler, D., Christoffersen, N. R., Nielsen, M. M., Asmar, F., Kooistra, S. M., Christophersen, N. S., Christensen, L. L., Borre, M., Sørensen, K. D., Andersen, L. D., Andersen, C. L., Hulleman, E., Wurdinger, T., Ralfkiær, E., Helin, K., Grønbæk, K., Ørntoft, T., Waszak, S. M., Dahan, O., … Pilpel, Y. (2014). A dual program for translation regulation in cellular proliferation and differentiation. Cell, 158(6), 1281–1292. https://doi.org/10.1016/j.cell.2014.08.011 Gonzalo, S., Kreienkamp, R., & Askjaer, P. (2017). Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing research reviews, 33, 18–29. https://doi.org/10.1016/j.arr.2016.06.007 Han, Y., Yan, C., Fishbain, S., Ivanov, I., & He, Y. (2018). Structural visualization of RNA polymerase III transcription machineries. Cell discovery, 4, 40. https://doi.org/10.1038/s41421-018-0044-z Harkema, L., Youssef, S. A., & de Bruin, A. (2016). Pathology of Mouse Models of Accelerated Aging. Veterinary pathology, 53(2), 366–389. https://doi.org/10.1177/0300985815625169 Hayflick L. (1974). The longevity of cultured human cells. Journal of the American Geriatrics Society, 22(1), 1–12. https://doi.org/10.1111/j.1532-5415.1974.tb02152.x Herranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., Georgilis, A., Montoya, A., Wolter, K., Dharmalingam, G., Faull, P., Carroll, T., Martínez-Barbera, J. P., Cutillas, P., Reisinger, F., Heikenwalder, M., … Gil, J. (2015). mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nature cell biology, 17(9), 1205–1217. https://doi.org/10.1038/ncb3225 Herranz, N., & Gil, J. (2018). Mechanisms and functions of cellular senescence. The Journal of clinical investigation, 128(4), 1238–1246. https://doi.org/10.1172/JCI95148 Hsu, A. L., Murphy, C. T., & Kenyon, C. (2003). Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science (New York, N.Y.), 300(5622), 1142–1145. https://doi.org/10.1126/science.1083701 Hughes, K. A., Alipaz, J. A., Drnevich, J. M., & Reynolds, R. M. (2002). A test of evolutionary theories of aging. Proceedings of the National Academy of Sciences of the United States of America, 99(22), 14286–14291. https://doi.org/10.1073/pnas.222326199 Jay, A. M., Conway, R. L., Thiffault, I., Saunders, C., Farrow, E., Adams, J., & Toriello, H. V. (2016). Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. American journal of medical genetics. Part A, 170(12), 3343–3346. https://doi.org/10.1002/ajmg.a.37960 Kipling, D., Davis, T., Ostler, E. L., & Faragher, R. G. (2004). What can progeroid syndromes tell us about human aging?. Science (New York, N.Y.), 305(5689), 1426–1431. https://doi.org/10.1126/science.1102587 Kirkland, J. L., & Tchkonia, T. (2017). Cellular Senescence: A Translational Perspective. EBioMedicine, 21, 21–28. https://doi.org/10.1016/j.ebiom.2017.04.013 Kirkwood, T. B., & Rose, M. R. (1991). Evolution of senescence: late survival sacrificed for reproduction. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 332(1262), 15–24. https://doi.org/10.1098/rstb.1991.0028 Kirkwood T. B. (1996). Human senescence. BioEssays : news and reviews in molecular, cellular and developmental biology, 18(12), 1009–1016. https://doi.org/10.1002/bies.950181211 Kong, D. H., Kim, Y. K., Kim, M. R., Jang, J. H., & Lee, S. (2018). Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. International journal of molecular sciences, 19(4), 1057. https://doi.org/10.3390/ijms19041057 Korniszewski, L., Nowak, R., Oknińska-Hoffmann, E., Skórka, A., Gieruszczak-Białek, D., & Sawadro-Rochowska, M. (2001). Wiedemann-Rautenstrauch (neonatal progeroid) syndrome: new case with normal telomere length in skin fibroblasts. American journal of medical genetics, 103(2), 144–148. https://doi.org/10.1002/ajmg.1530 Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004). Ink4a/Arf expression is a biomarker of aging. The Journal of clinical investigation, 114(9), 1299–1307. https://doi.org/10.1172/JCI22475 Lessel, D., Ozel, A. B., Campbell, S. E., Saadi, A., Arlt, M. F., McSweeney, K. M., Plaiasu, V., Szakszon, K., Szőllős, A., Rusu, C., Rojas, A. J., Lopez-Valdez, J., Thiele, H., Nürnberg, P., Nickerson, D. A., Bamshad, M. J., Li, J. Z., Kubisch, C., Glover, T. W., & Gordon, L. B. (2018). Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Human genetics, 137(11-12), 921–939. https://doi.org/10.1007/s00439-018-1957-1 Levi, N., Papismadov, N., Solomonov, I., Sagi, I., & Krizhanovsky, V. (2020). The ECM path of senescence in aging: components and modifiers. The FEBS journal, 287(13), 2636–2646. https://doi.org/10.1111/febs.15282 Li, P., Gan, Y., Xu, Y., Song, L., Wang, L., Ouyang, B., Zhang, C., & Zhou, Q. (2017). The inflammatory cytokine TNF-α promotes the premature senescence of rat nucleus pulposus cells via the PI3K/Akt signaling pathway. Scientific reports, 7, 42938. https://doi.org/10.1038/srep42938 Lieberman J. (2018). Unveiling the RNA World. The New England journal of medicine, 379(13), 1278–1280. https://doi.org/10.1056/NEJMcibr1808725 López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039 López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278. https://doi.org/10.1016/j.cell.2022.11.001 Majewski, J., Schwartzentruber, J., Lalonde, E., Montpetit, A., & Jabado, N. (2011). What can exome sequencing do for you?. Journal of medical genetics, 48(9), 580–589. https://doi.org/10.1136/jmedgenet-2011-100223 Martin G. M. (1982). Syndromes of accelerated aging. National Cancer Institute monograph, 60, 241–247. Martin G. M. (2005). Genetic modulation of senescent phenotypes in Homo sapiens. Cell, 120(4), 523–532. https://doi.org/10.1016/j.cell.2005.01.031 Mathon, N. F., Malcolm, D. S., Harrisingh, M. C., Cheng, L., & Lloyd, A. C. (2001). Lack of replicative senescence in normal rodent glia. Science (New York, N.Y.), 291(5505), 872–875. https://doi.org/10.1126/science.1056782 Morales, L. C., Arboleda, G., Rodríguez, Y., Forero, D. A., Ramírez, N., Yunis, J. J., & Arboleda, H. (2009). Absence of Lamin A/C gene mutations in four Wiedemann-Rautenstrauch syndrome patients. American journal of medical genetics. Part A, 149A(12), 2695–2699. https://doi.org/10.1002/ajmg.a.33090 Mukherjee, S., Date, A., Patravale, V., Korting, H. C., Roeder, A., & Weindl, G. (2006). Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clinical interventions in aging, 1(4), 327–348. https://doi.org/10.2147/ciia.2006.1.4.327 Nunes, V. S., & Moretti, N. S. (2017). Nuclear subcompartments: an overview. Cell biology international, 41(1), 2–7. https://doi.org/10.1002/cbin.10703 Ovadya, Y., & Krizhanovsky, V. (2014). Senescent cells: SASPected drivers of age-related pathologies. Biogerontology, 15(6), 627–642. https://doi.org/10.1007/s10522-014-9529-9 Paolacci, S., Bertola, D., Franco, J., Mohammed, S., Tartaglia, M., Wollnik, B., & Hennekam, R. C. (2017). Wiedemann-Rautenstrauch syndrome: A phenotype analysis. American journal of medical genetics. Part A, 173(7), 1763–1772. https://doi.org/10.1002/ajmg.a.38246 Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmüller, J., Arboleda, G., Beleggia, F., Bruselles, A., Ciolfi, A., Gillessen-Kaesbach, G., Krieg, T., Mohammed, S., Müller, C., Novelli, A., Ortega, J., … Hennekam, R. C. (2018). Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. Journal of medical genetics, 55(12), 837–846. https://doi.org/10.1136/jmedgenet-2018-105528 Partridge, L., & Gems, D. (2002). Mechanisms of ageing: public or private?. Nature reviews. Genetics, 3(3), 165–175. https://doi.org/10.1038/nrg753 Pivnick, E. K., Angle, B., Kaufman, R. A., Hall, B. D., Pitukcheewanont, P., Hersh, J. H., Fowlkes, J. L., Sanders, L. P., O'Brien, J. M., Carroll, G. S., Gunther, W. M., Morrow, H. G., Burghen, G. A., & Ward, J. C. (2000). Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: report of five new cases and review. American journal of medical genetics, 90(2), 131–140. Plotnikov, A., Zehorai, E., Procaccia, S., & Seger, R. (2011). The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochimica et biophysica acta, 1813(9), 1619–1633. https://doi.org/10.1016/j.bbamcr.2010.12.012 Puzianowska-Kuznicka, M., & Kuznicki, J. (2005). Genetic alterations in accelerated ageing syndromes. Do they play a role in natural ageing?. The international journal of biochemistry & cell biology, 37(5), 947–960. https://doi.org/10.1016/j.biocel.2004.10.011 Rautenstrauch, T., & Snigula, F. (1977). Progeria: A cell culture study and clinical report of familial incidence. European Journal of Pediatrics, 124(2), 101– 111. https://doi.org/10.1007/BF00477545 Rautenstrauch, T., Snigula, F., & Wiedemann, H. R. (1994). Neonatales progeroides Syndrom (Wiedemann-Rautenstrauch). Eine follow-up-Studie [Neonatal progeroid syndrome (Wiedemann-Rautenstrauch). A follow-up study]. Klinische Padiatrie, 206(6), 440–443. https://doi.org/10.1055/s-2008-1046647 Ressler, S., Bartkova, J., Niederegger, H., Bartek, J., Scharffetter-Kochanek, K., Jansen-Dürr, P., & Wlaschek, M. (2006). p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging cell, 5(5), 379–389. https://doi.org/10.1111/j.1474-9726.2006.00231.x Ricklefs R. E. (1998). Evolutionary theories of aging: confirmation of a fundamental prediction, with implications for the genetic basis and evolution of life span. The American naturalist, 152(1), 24–44. https://doi.org/10.1086/286147 Romá-Mateo, C., Seco-Cervera, M., Ibáñez-Cabellos, J. S., Pérez, G., Berenguer-Pascual, E., Rodríguez, L. R., & García-Giménez, J. L. (2018). Oxidative Stress and the Epigenetics of Cell Senescence: Insights from Progeroid Syndromes. Current pharmaceutical design, 24(40), 4755–4770. https://doi.org/10.2174/1381612824666190114164117 Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., & Matsumoto, N. (2011). Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. American journal of human genetics, 89(5), 644–651. https://doi.org/10.1016/j.ajhg.2011.10.003 Scaffidi, P., & Misteli, T. (2006). Lamin A-dependent nuclear defects in human aging. Science (New York, N.Y.), 312(5776), 1059–1063. https://doi.org/10.1126/science.1127168 Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelson, T., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., & Zhang, F. (2014). Genome-scale CRISPR-Cas9 knockout screening in human cells. Science (New York, N.Y.), 343(6166), 84–87. https://doi.org/10.1126/science.1247005 Sherr, C. J., & DePinho, R. A. (2000). Cellular senescence: mitotic clock or culture shock?. Cell, 102(4), 407–410. https://doi.org/10.1016/s0092-8674(00)00046-5 Shimojima, K., Shimada, S., Tamasaki, A., Akaboshi, S., Komoike, Y., Saito, A., Furukawa, T., & Yamamoto, T. (2014). Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination. Brain & development, 36(4), 315–321. https://doi.org/10.1016/j.braindev.2013.04.011 Sinclair, D. A., & Guarente, L. (1997). Extrachromosomal rDNA circles--a cause of aging in yeast. Cell, 91(7), 1033–1042. https://doi.org/10.1016/s0092-8674(00)80493-6 Thiffault, I., Wolf, N. I., Forget, D., Guerrero, K., Tran, L. T., Choquet, K., Lavallée-Adam, M., Poitras, C., Brais, B., Yoon, G., Sztriha, L., Webster, R. I., Timmann, D., van de Warrenburg, B. P., Seeger, J., Zimmermann, A., Máté, A., Goizet, C., Fung, E., van der Knaap, M. S., Bernard, G. (2015). Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nature communications, 6, 7623. https://doi.org/10.1038/ncomms8623 Thorey, F., Jäger, M., Seller, K., Krauspe, R., & Wild, A. (2003). Kyphoskoliose beim Wiedemann-Rautenstrauch-Syndrom (neonatales Progerie Syndrom) [Kyphoscoliosis in Wiedemann-Rautenstrauch-syndrome (neonatal progeroid syndrome)]. Zeitschrift fur Orthopadie und ihre Grenzgebiete, 141(3), 341–344. https://doi.org/10.1055/s-2003-40084 Tiku, V., & Antebi, A. (2018). Nucleolar Function in Lifespan Regulation. Trends in cell biology, 28(8), 662–672. https://doi.org/10.1016/j.tcb.2018.03.007 Timmers, P. R. H. J., Tiys, E. S., Sakaue, S., Akiyama, M., Kiiskinen, T. T. J., Zhou, W., Hwang, S. J., Yao, C., Biobank Japan Project, FinnGen, Deelen, J., Levy, D., Ganna, A., Kamatani, Y., Okada, Y., Joshi, P. K., Wilson, J. F., & Tsepilov, Y. A. (2022). Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging. Nature aging, 2(1), 19–30. https://doi.org/10.1038/s43587-021-00159-8 Troen B. R. (2003). The biology of aging. The Mount Sinai journal of medicine, New York, 70(1), 3–22. Turowski, T. W., & Tollervey, D. (2016). Transcription by RNA polymerase III: insights into mechanism and regulation. Biochemical Society transactions, 44(5), 1367–1375. https://doi.org/10.1042/BST20160062 Ungewitter, E., & Scrable, H. (2009). Antagonistic pleiotropy and p53. Mechanisms of ageing and development, 130(1-2), 10–17. https://doi.org/10.1016/j.mad.2008.06.002 Varani, J., Warner, R. L., Gharaee-Kermani, M., Phan, S. H., Kang, S., Chung, J. H., Wang, Z. Q., Datta, S. C., Fisher, G. J., & Voorhees, J. J. (2000). Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. The Journal of investigative dermatology, 114(3), 480–486. https://doi.org/10.1046/j.1523-1747.2000.00902.x Velasquez-Mendez K. (2019). Analysis of POLR3A gene expression in fibroblasts from Wiedemann-Rautenstrauch Syndrome patients. Autonomous University of Barcelona. Vitale, G., Salvioli, S., & Franceschi, C. (2013). Oxidative stress and the ageing endocrine system. Nature reviews. Endocrinology, 9(4), 228–240. https://doi.org/10.1038/nrendo.2013.29 Wang, M., & Lemos, B. (2019). Ribosomal DNA harbors an evolutionarily conserved clock of biological aging. Genome research, 29(3), 325–333. https://doi.org/10.1101/gr.241745.118 Wang, Z., Gerstein, M., & Snyder, M. (2009). RNA-Seq: a revolutionary tool for transcriptomics. Nature reviews. Genetics, 10(1), 57–63. https://doi.org/10.1038/nrg2484 Wang, T., Wei, J. J., Sabatini, D. M., & Lander, E. S. (2014). Genetic screens in human cells using the CRISPR-Cas9 system. Science (New York, N.Y.), 343(6166), 80–84. https://doi.org/10.1126/science.1246981 Warner, H. R., & Sierra, F. (2003). Models of accelerated ageing can be informative about the molecular mechanisms of ageing and/or age-related pathology. Mechanisms of ageing and development, 124(5), 581–587. https://doi.org/10.1016/s0047-6374(03)00008-3 Warrenburg, B. P., Seeger, J., Zimmermann, A., Máté, A., Goizet, C., Fung, E., van der Knaap, M. S., … Bernard, G. (2015). Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nature communications, 6, 7623. https://doi.org/10.1038/ncomms8623 Wiedemann H. R. (1979). An unidentified neonatal progeroid syndrome: follow-up report. European journal of pediatrics, 130(1), 65–70. https://doi.org/10.1007/BF00441901 Wolf, N. I., Vanderver, A., van Spaendonk, R. M., Schiffmann, R., Brais, B., Bugiani, M., Sistermans, E., Catsman-Berrevoets, C., Kros, J. M., Pinto, P. S., Pohl, D., Tirupathi, S., Strømme, P., de Grauw, T., Fribourg, S., Demos, M., Pizzino, A., Naidu, S., Guerrero, K., van der Knaap, M. S., … 4H Research Group (2014). Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology, 83(21), 1898–1905. https://doi.org/10.1212/WNL.0000000000001002 Xu, Y., Li, N., Xiang, R., & Sun, P. (2014). Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends in biochemical sciences, 39(6), 268–276. https://doi.org/10.1016/j.tibs.2014.04.004 Yosef, R., Pilpel, N., Papismadov, N., Gal, H., Ovadya, Y., Vadai, E., Miller, S., Porat, Z., Ben-Dor, S., & Krizhanovsky, V. (2017). p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling. The EMBO journal, 36(15), 2280–2295. https://doi.org/10.15252/embj.201695553 Yousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., Nair, R. V., Bonanno, L. N., Yang, A. C., Peterson, T., Hadeiba, H., Merkel, T., Körbelin, J., Schwaninger, M., Buckwalter, M. S., Quake, S. R., … Wyss-Coray, T. (2019). Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nature medicine, 25(6), 988–1000. https://doi.org/10.1038/s41591-019-0440-4 Zarei, A., Razban, V., Hosseini, S. E., & Tabei, S. M. B. (2019). Creating cell and animal models of human disease by genome editing using CRISPR/Cas9. The journal of gene medicine, 21(4), e3082. https://doi.org/10.1002/jgm.3082
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dc.format.extent.spa.fl_str_mv	102 páginas
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dc.publisher.spa.fl_str_mv	Universidad Nacional de Colombia
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dc.publisher.faculty.spa.fl_str_mv	Facultad de Ciencias
dc.publisher.place.spa.fl_str_mv	Bogotá, Colombia
dc.publisher.branch.spa.fl_str_mv	Universidad Nacional de Colombia - Sede Bogotá
institution	Universidad Nacional de Colombia
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spelling	Atribución-NoComercial-SinDerivadas 4.0 Internacionalhttp://creativecommons.org/licenses/by-nc-nd/4.0/info:eu-repo/semantics/openAccesshttp://purl.org/coar/access_right/c_abf2Arboleda, Gonzalo53ff3116cb55de18e34deb60d8c31a23600Santos-Gil, Daniel440e19a7e7bc8597508ec177b1c46614600Muerte CelularGrupo de Neurociencias-Universidad Nacional de ColombiaSantos-Gil, Daniel [0000-0002-1309-8081]Santos-Gil, Daniel F. [https://scienti.minciencias.gov.co/cvlac/visualizador/generarCurriculoCv.do?cod_rh=0001688007]2023-10-30T20:53:20Z2023-10-30T20:53:20Z2023-06-26https://repositorio.unal.edu.co/handle/unal/84852Universidad Nacional de ColombiaRepositorio Institucional Universidad Nacional de Colombiahttps://repositorio.unal.edu.co/ilustraciones, diagramas,El síndrome de Wiedemann-Rautenstracuh (WRS) ha sido caracterizado como una entidad progeroide neonatal o de envejecimiento prematuro. Este grupo de síndromes tienen en común cambios monogenéticos que contribuyen a la aparición de fenotipos de envejecimiento que se evidencian en distintas etapas del desarrollo del individuo e in vitro presentan senescencia celular prematura. El WRS presenta un patrón de herencia autosómica recesiva cuya etiología es poco conocida. Recientemente se han descrito mutaciones en el gen POLR3A que codifica la subunidad catalítica A de la RNA polimerasa III. Esta enzima sintetiza un grupo de RNAs pequeños no codificantes (snRNAs), entre ellos tRNAs, 5S rRNA y U6 snRNA, que son importantes para el correcto funcionamiento del nucleolo, el ensamblaje de ribosomas, la traducción de proteínas y el metabolismo celular. Se planteó como objetivo describir las características celulares y moleculares de los fibroblastos WRS y la relación con un modelo de pérdida de función. Métodos: Se cultivaron fibroblastos primarios de dos pacientes WRS con variantes monoalélicas: WRS1[POLR3A c.3772_3773delCT (p. Leu1258Glyfs12)] y WRS2 [POLR3A c.3G>T (p. Met1Leu)]; fibroblastos knockout (KO) [POLR3A -/-] y fibroblastos control [POLR3A +/+]. Se determinó la expresión global de RNA mediante RNAseq, identificando los genes diferencialmente expresados de cada conjunto de datos, los cuales fueron filtrados y analizados según los criterios de exclusión a nivel estadístico y biológico. Se llevó a cabo un análisis de enriquecimiento funcional con las bases de datos Gene Ontology (GO) y Kyoto Encyclopedia of Genes and Genomes (KEGG). Por RTqPCR, inmunofluorescencia y western blot, se analizaron los patrones de expresión de POLR3A, la expresión y localización de marcadores nucleolares y los niveles de marcadores de senescencia celular. Resultados: Se observó que hay un desbalance en la transcripción de los genes diana de la RNA Polimerasa III. Se encontraron perfiles de expresión diferenciales y se identificaron los genes diferencialmente expresados (DEGs) de cada conjunto de datos, siendo 204 en común entre el fenotipo WRS y 147 con la condición KO. El análisis de enriquecimiento funcional mostró sobrerrepresentadas múltiples categorías, entre ellas la vía PI3K-Akt, la interacción del receptor con la matriz extracelular, el metabolismo del retinol y la regulación de la respuesta inflamatoria. Se detectó una mayor área de inmunoreactividad de los componentes nucleolares en los fibroblastos WRS, mientras que el grupo KO muestra una reducción; a nivel transcripcional y traduccional, hay un desbalance de los distintos componentes estructurales, acompañado de la reducción de la síntesis de los precursores ribosomales. Por último, se encontró una regulación al alza de los marcadores de senescencia celular P53/P21, P16/RB y GLB1. Conclusión: Las células WRS experimentan un proceso de senescencia celular prematura asociado a las mutaciones de POLR3A que conducen a una alteración de su función transcripcional. Esto resulta en un aumento en el área nucleolar, un desequilibrio en la producción de los componentes nucleolares y una alteración en la biogénesis ribosomal. Además, el análisis de enriquecimiento funcional reveló que múltiples vías de señalización están comprometidas como la supervivencia celular, la interacción y organización de la matriz extracelular y regulación de la respuesta inflamatoria. Estos hallazgos contribuyen a mejorar nuestra comprensión de los mecanismos subyacentes del WRS, que explican la alteración funcional de POLR3A y que dan lugar al fenotipo de envejecimiento prematuro y senescencia celular. También, amplían nuestra comprensión del panorama funcional del complejo RNA Polimerasa III en diversos componentes celulares, procesos biológicos y funciones moleculares. (Texto tomado de la fuente)Wiedemann-Rautenstracuh Syndrome (WRS) has been characterized as a neonatal progeroid entity or premature aging disorder. This group of syndromes share monogenetic changes that contribute to the emergence of aging phenotypes manifested at different stages of individual development and display premature cellular senescence in vitro. WRS follows an autosomal recessive inheritance pattern, and its etiology is poorly understood. Recently, mutations in the POLR3A gene, which encodes the catalytic subunit A of RNA polymerase III, have been described. This enzyme synthesizes a group of small non-coding RNAs (snRNAs), including tRNAs, 5S rRNA, and U6 snRNA, which are crucial for proper nucleolar function, ribosome assembly, protein translation, and cellular metabolism. The objective of this study was to describe the cellular and molecular characteristics of WRS fibroblasts and their relationship with a loss-of-function model. Methods: Primary fibroblasts were cultured from two WRS patients with monoallelic variants: WRS1 [POLR3A c.3772_3773delCT (p. Leu1258Glyfs12)] and WRS2 [POLR3A c.3G>T (p. Met1Leu)], as well as knockout (KO) fibroblasts [POLR3A -/-] and control fibroblasts [POLR3A +/+] were included. Global RNA expression was determined using RNAseq, identifying the differentially expressed genes in each dataset, which were filtered and analyzed based on statistical and biological exclusion criteria. Functional enrichment analysis was performed using the Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) databases. Expression patterns of POLR3A, nucleolar marker expression and localization, and cellular senescence markers were analyzed using RT-qPCR, immunofluorescence, and western blotting. Results: It was observed that there is an imbalance in the transcription of target genes of RNA Polymerase III. Differential expression profiles were found, and the differentially expressed genes (DEGs) were identified in each dataset, with 204 genes in common between the WRS phenotype and 147 genes compared to the KO condition. Functional enrichment analysis showed multiple overrepresented categories, including the PI3K-Akt pathway, receptor interaction with the extracellular matrix, retinol metabolism, and regulation of the inflammatory response. A greater area of immunoreactivity in nucleolar components was detected in WRS fibroblasts, while the KO group showed a reduction. At the transcriptional and translational level, there was an imbalance in different structural components, accompanied by a decrease in the synthesis of ribosomal precursors. Finally, an upregulation of cellular senescence markers P53/P21, P16/RB, and GLB1 was found. Conclusion: WRS cells undergo a process of premature cellular senescence associated with POLR3A mutations, which lead to an alteration in their transcriptional function. This results in an increase in nucleolar area, an imbalance in the production of nucleolar components, and a disruption in ribosomal biogenesis. Furthermore, the functional enrichment analysis revealed that multiple signaling pathways are compromised, including cell survival, interaction and organization of the extracellular matrix, and regulation of the inflammatory response. These findings contribute to improving our understanding of the underlying mechanisms of WRS, explaining the functional impairment of POLR3A, and resulting in the phenotype of premature aging and cellular senescence. They also broaden our understanding of the functional landscape of the RNA Polymerase III complex in various cellular components, biological processes, and molecular functions.MaestríaMagíster en Ciencias - BioquímicaBiología del envejecimiento102 páginasapplication/pdfspaUniversidad Nacional de ColombiaBogotá - Ciencias - Maestría en Ciencias - BioquímicaFacultad de CienciasBogotá, ColombiaUniversidad Nacional de Colombia - Sede Bogotá610 - Medicina y salud::616 - Enfermedades570 - Biología::572 - Bioquímica570 - Biología::576 - Genética y evoluciónMedicina molecularMolecular MedicineSíndrome ProgeroideSenescencia CelularEnvejecimiento HumanoRNA Polimerasa IIINucleoloPOLR3ARNA-seqAgingEstudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)Cellular and Molecular Study of the POLR3A Gene Associated with Neonatal Progeroid Syndrome (Wiedemann-Rautenstrauch Syndrome)Trabajo de grado - Maestríainfo:eu-repo/semantics/masterThesisinfo:eu-repo/semantics/acceptedVersionTexthttp://purl.org/redcol/resource_type/TMAdams, D. R., & Eng, C. M. (2018). Next-Generation Sequencing to Diagnose Suspected Genetic Disorders. The New England journal of medicine, 379(14), 1353–1362. https://doi.org/10.1056/NEJMra1711801Allsopp, R. C., Chang, E., Kashefi-Aazam, M., Rogaev, E. I., Piatyszek, M. A., Shay, J. W., & Harley, C. B. (1995). Telomere shortening is associated with cell division in vitro and in vivo. Experimental cell research, 220(1), 194–200. https://doi.org/10.1006/excr.1995.1306Arboleda, H., Quintero, L., & Yunis, E. (1997). Wiedemann-Rautenstrauch neonatal progeroid syndrome: report of three new patients. Journal of medical genetics, 34(5), 433–437. https://doi.org/10.1136/jmg.34.5.433Arboleda, G., Morales, L. C., Quintero, L., & Arboleda, H. (2011). Neonatal progeroid syndrome (Wiedemann-Rautenstrauch syndrome): report of three affected sibs. American journal of medical genetics. Part A, 155A(7), 1712–1715. https://doi.org/10.1002/ajmg.a.34019Arboleda, H., & Arboleda, G. (2005). Follow-up study of Wiedemann-Rautenstrauch syndrome: long-term survival and comparison with Rautenstrauch's patient "G". Birth defects research. Part A, Clinical and molecular teratology, 73(8), 562–568. https://doi.org/10.1002/bdra.20166Arimbasseri, A. G., & Maraia, R. J. (2016). RNA Polymerase III Advances: Structural and tRNA Functional Views. Trends in biochemical sciences, 41(6), 546–559. https://doi.org/10.1016/j.tibs.2016.03.003Astle, M. V., Hannan, K. M., Ng, P. Y., Lee, R. S., George, A. J., Hsu, A. K., Haupt, Y., Hannan, R. D., & Pearson, R. B. (2012). AKT induces senescence in human cells via mTORC1 and p53 in the absence of DNA damage: implications for targeting mTOR during malignancy. Oncogene, 31(15), 1949–1962. https://doi.org/10.1038/onc.2011.394Austad, S. N., & Hoffman, J. M. (2018). Is antagonistic pleiotropy ubiquitous in aging biology? Evolution, medicine, and public health, 2018(1), 287–294. https://doi.org/10.1093/emph/eoy033Azmanov, D. N., Siira, S. J., Chamova, T., Kaprelyan, A., Guergueltcheva, V., Shearwood, A. J., Liu, G., Morar, B., Rackham, O., Bynevelt, M., Grudkova, M., Kamenov, Z., Svechtarov, V., Tournev, I., Kalaydjieva, L., & Filipovska, A. (2016). Transcriptome-wide effects of a POLR3A gene mutation in patients with an unusual phenotype of striatal involvement. Human molecular genetics, 25(19), 4302–4314. https://doi.org/10.1093/hmg/ddw263Báez-Becerra, C. T., Valencia-Rincón, E., Velásquez-Méndez, K., Ramírez-Suárez, N. J., Guevara, C., Sandoval-Hernandez, A., Arboleda-Bustos, C. E., Olivos-Cisneros, L., Gutiérrez-Ospina, G., Arboleda, H., & Arboleda, G. (2020). Nucleolar disruption, activation of P53 and premature senescence in POLR3A-mutated Wiedemann-Rautenstrauch syndrome fibroblasts. Mechanisms of ageing and development, 192, 111360. https://doi.org/10.1016/j.mad.2020.111360Barrangou, R., Fremaux, C., Deveau, H., Richards, M., Boyaval, P., Moineau, S., Romero, D. A., & Horvath, P. (2007). CRISPR provides acquired resistance against viruses in prokaryotes. Science (New York, N.Y.), 315(5819), 1709–1712. https://doi.org/10.1126/science.1138140Bernard, G., Chouery, E., Putorti, M. L., Tétreault, M., Takanohashi, A., Carosso, G., Clément, I., Boespflug-Tanguy, O., Rodriguez, D., Delague, V., Abou Ghoch, J., Jalkh, N., Dorboz, I., Fribourg, S., Teichmann, M., Megarbane, A., Schiffmann, R., Vanderver, A., & Brais, B. (2011). Mutations of POLR3A encoding a catalytic subunit of RNA polymerase Pol III cause a recessive hypomyelinating leukodystrophy. American journal of human genetics, 89(3), 415–423. https://doi.org/10.1016/j.ajhg.2011.07.014Boulon, S., Westman, B. J., Hutten, S., Boisvert, F. M., & Lamond, A. I. (2010). The nucleolus under stress. Molecular cell, 40(2), 216–227. https://doi.org/10.1016/j.molcel.2010.09.024Brown W. T. (1992). Progeria: a human-disease model of accelerated aging. The American journal of clinical nutrition, 55(6 Suppl), 1222S–1224S. https://doi.org/10.1093/ajcn/55.6.1222SBurtner, C. R., & Kennedy, B. K. (2010). Progeria syndromes and ageing: what is the connection?. Nature reviews. Molecular cell biology, 11(8), 567–578. https://doi.org/10.1038/nrm2944Buchwalter, A., & Hetzer, M. W. (2017). Nucleolar expansion and elevated protein translation in premature aging. Nature communications, 8(1), 328. https://doi.org/10.1038/s41467-017-00322-zBurke, B., & Stewart, C. L. (2002). Life at the edge: the nuclear envelope and human disease. Nature reviews. Molecular cell biology, 3(8), 575–585. https://doi.org/10.1038/nrm879Campisi J. (1997). The biology of replicative senescence. European journal of cancer (Oxford, England : 1990), 33(5), 703–709. https://doi.org/10.1016/S0959-8049(96)00058-5Campisi J. (1998). The role of cellular senescence in skin aging. The journal of investigative dermatology. Symposium proceedings, 3(1), 1–5.Campisi J. (2005). Suppressing cancer: the importance of being senescent. Science (New York, N.Y.), 309(5736), 886–887. https://doi.org/10.1126/science.1116801Campisi, J., & Robert, L. (2014). Cell senescence: role in aging and age-related diseases. Interdisciplinary topics in gerontology, 39, 45–61. https://doi.org/10.1159/000358899Cao, H., & Hegele, R. A. (2003). LMNA is mutated in Hutchinson-Gilford progeria (MIM 176670) but not in Wiedemann-Rautenstrauch progeroid syndrome (MIM 264090). Journal of human genetics, 48(5), 271–274. https://doi.org/10.1007/s10038-003-0025-3Carter, C. S., Sonntag, W. E., Onder, G., & Pahor, M. (2002). Physical performance and longevity in aged rats. The journals of gerontology. Series A, Biological sciences and medical sciences, 57(5), B193–B197. https://doi.org/10.1093/gerona/57.5.b193Childs, B. G., Durik, M., Baker, D. J., & van Deursen, J. M. (2015). Cellular senescence in aging and age-related disease: from mechanisms to therapy. Nature medicine, 21(12), 1424–1435. https://doi.org/10.1038/nm.4000Ciganda, M., & Williams, N. (2011). Eukaryotic 5S rRNA biogenesis. Wiley interdisciplinary reviews. RNA, 2(4), 523–533. https://doi.org/10.1002/wrna.74Clancy, D. J., Gems, D., Hafen, E., Leevers, S. J., & Partridge, L. (2002). Dietary restriction in long-lived dwarf flies. Science (New York, N.Y.), 296(5566), 319. https://doi.org/10.1126/science.1069366Coppé, J. P., Desprez, P. Y., Krtolica, A., & Campisi, J. (2010). The senescence-associated secretory phenotype: the dark side of tumor suppression. Annual review of pathology, 5, 99–118. https://doi.org/10.1146/annurev-pathol-121808-102144Cole, J. R., Wang, Q., Fish, J. A., Chai, B., McGarrell, D. M., Sun, Y., Brown, C. T., Porras-Alfaro, A., Kuske, C. R., & Tiedje, J. M. (2014). Ribosomal Database Project: data and tools for high throughput rRNA analysis. Nucleic acids research, 42(Database issue), D633–D642.Csoka, A. B., English, S. B., Simkevich, C. P., Ginzinger, D. G., Butte, A. J., Schatten, G. P., Rothman, F. G., & Sedivy, J. M. (2004). Genome-scale expression profiling of Hutchinson-Gilford progeria syndrome reveals widespread transcriptional misregulation leading to mesodermal/mesenchymal defects and accelerated atherosclerosis. Aging cell, 3(4), 235–243. https://doi.org/10.1111/j.1474-9728.2004.00105.xDieci, G., Fiorino, G., Castelnuovo, M., Teichmann, M., & Pagano, A. (2007). The expanding RNA polymerase III transcriptome. Trends in genetics : TIG, 23(12), 614–622. https://doi.org/10.1016/j.tig.2007.09.001Dimri, G. P., Lee, X., Basile, G., Acosta, M., Scott, G., Roskelley, C., Medrano, E. E., Linskens, M., Rubelj, I., & Pereira-Smith, O. (1995). A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proceedings of the National Academy of Sciences of the United States of America, 92(20), 9363–9367. https://doi.org/10.1073/pnas.92.20.9363Ellis, J. A., & Shackleton, S. (2011). Nuclear envelope disease and chromatin organization. Biochemical Society transactions, 39(6), 1683–1686. https://doi.org/10.1042/BST20110744Eriksson, M., Brown, W. T., Gordon, L. B., Glynn, M. W., Singer, J., Scott, L., Erdos, M. R., Robbins, C. M., Moses, T. Y., Berglund, P., Dutra, A., Pak, E., Durkin, S., Csoka, A. B., Boehnke, M., Glover, T. W., & Collins, F. S. (2003). Recurrent de novo point mutations in lamin A cause Hutchinson-Gilford progeria syndrome. Nature, 423(6937), 293–298. https://doi.org/10.1038/nature01629Franceschi, C., Garagnani, P., Parini, P., Giuliani, C., & Santoro, A. (2018). Inflammaging: a new immune-metabolic viewpoint for age-related diseases. Nature reviews. Endocrinology, 14(10), 576–590. https://doi.org/10.1038/s41574-018-0059-4Freund, A., Patil, C. K., & Campisi, J. (2011). p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. The EMBO journal, 30(8), 1536–1548. https://doi.org/10.1038/emboj.2011.69George, S., Rochford, J. J., Wolfrum, C., Gray, S. L., Schinner, S., Wilson, J. C., Soos, M. A., Murgatroyd, P. R., Williams, R. M., Acerini, C. L., Dunger, D. B., Barford, D., Umpleby, A. M., Wareham, N. J., Davies, H. A., Schafer, A. J., Stoffel, M., O'Rahilly, S., & Barroso, I. (2004). A family with severe insulin resistance and diabetes due to a mutation in AKT2. Science (New York, N.Y.), 304(5675), 1325–1328. https://doi.org/10.1126/science.1096706Gingold, H., Tehler, D., Christoffersen, N. R., Nielsen, M. M., Asmar, F., Kooistra, S. M., Christophersen, N. S., Christensen, L. L., Borre, M., Sørensen, K. D., Andersen, L. D., Andersen, C. L., Hulleman, E., Wurdinger, T., Ralfkiær, E., Helin, K., Grønbæk, K., Ørntoft, T., Waszak, S. M., Dahan, O., … Pilpel, Y. (2014). A dual program for translation regulation in cellular proliferation and differentiation. Cell, 158(6), 1281–1292. https://doi.org/10.1016/j.cell.2014.08.011Gonzalo, S., Kreienkamp, R., & Askjaer, P. (2017). Hutchinson-Gilford Progeria Syndrome: A premature aging disease caused by LMNA gene mutations. Ageing research reviews, 33, 18–29. https://doi.org/10.1016/j.arr.2016.06.007Han, Y., Yan, C., Fishbain, S., Ivanov, I., & He, Y. (2018). Structural visualization of RNA polymerase III transcription machineries. Cell discovery, 4, 40. https://doi.org/10.1038/s41421-018-0044-zHarkema, L., Youssef, S. A., & de Bruin, A. (2016). Pathology of Mouse Models of Accelerated Aging. Veterinary pathology, 53(2), 366–389. https://doi.org/10.1177/0300985815625169Hayflick L. (1974). The longevity of cultured human cells. Journal of the American Geriatrics Society, 22(1), 1–12. https://doi.org/10.1111/j.1532-5415.1974.tb02152.xHerranz, N., Gallage, S., Mellone, M., Wuestefeld, T., Klotz, S., Hanley, C. J., Raguz, S., Acosta, J. C., Innes, A. J., Banito, A., Georgilis, A., Montoya, A., Wolter, K., Dharmalingam, G., Faull, P., Carroll, T., Martínez-Barbera, J. P., Cutillas, P., Reisinger, F., Heikenwalder, M., … Gil, J. (2015). mTOR regulates MAPKAPK2 translation to control the senescence-associated secretory phenotype. Nature cell biology, 17(9), 1205–1217. https://doi.org/10.1038/ncb3225Herranz, N., & Gil, J. (2018). Mechanisms and functions of cellular senescence. The Journal of clinical investigation, 128(4), 1238–1246. https://doi.org/10.1172/JCI95148Hsu, A. L., Murphy, C. T., & Kenyon, C. (2003). Regulation of aging and age-related disease by DAF-16 and heat-shock factor. Science (New York, N.Y.), 300(5622), 1142–1145. https://doi.org/10.1126/science.1083701Hughes, K. A., Alipaz, J. A., Drnevich, J. M., & Reynolds, R. M. (2002). A test of evolutionary theories of aging. Proceedings of the National Academy of Sciences of the United States of America, 99(22), 14286–14291. https://doi.org/10.1073/pnas.222326199Jay, A. M., Conway, R. L., Thiffault, I., Saunders, C., Farrow, E., Adams, J., & Toriello, H. V. (2016). Neonatal progeriod syndrome associated with biallelic truncating variants in POLR3A. American journal of medical genetics. Part A, 170(12), 3343–3346. https://doi.org/10.1002/ajmg.a.37960Kipling, D., Davis, T., Ostler, E. L., & Faragher, R. G. (2004). What can progeroid syndromes tell us about human aging?. Science (New York, N.Y.), 305(5689), 1426–1431. https://doi.org/10.1126/science.1102587Kirkland, J. L., & Tchkonia, T. (2017). Cellular Senescence: A Translational Perspective. EBioMedicine, 21, 21–28. https://doi.org/10.1016/j.ebiom.2017.04.013Kirkwood, T. B., & Rose, M. R. (1991). Evolution of senescence: late survival sacrificed for reproduction. Philosophical transactions of the Royal Society of London. Series B, Biological sciences, 332(1262), 15–24. https://doi.org/10.1098/rstb.1991.0028Kirkwood T. B. (1996). Human senescence. BioEssays : news and reviews in molecular, cellular and developmental biology, 18(12), 1009–1016. https://doi.org/10.1002/bies.950181211Kong, D. H., Kim, Y. K., Kim, M. R., Jang, J. H., & Lee, S. (2018). Emerging Roles of Vascular Cell Adhesion Molecule-1 (VCAM-1) in Immunological Disorders and Cancer. International journal of molecular sciences, 19(4), 1057. https://doi.org/10.3390/ijms19041057Korniszewski, L., Nowak, R., Oknińska-Hoffmann, E., Skórka, A., Gieruszczak-Białek, D., & Sawadro-Rochowska, M. (2001). Wiedemann-Rautenstrauch (neonatal progeroid) syndrome: new case with normal telomere length in skin fibroblasts. American journal of medical genetics, 103(2), 144–148. https://doi.org/10.1002/ajmg.1530Krishnamurthy, J., Torrice, C., Ramsey, M. R., Kovalev, G. I., Al-Regaiey, K., Su, L., & Sharpless, N. E. (2004). Ink4a/Arf expression is a biomarker of aging. The Journal of clinical investigation, 114(9), 1299–1307. https://doi.org/10.1172/JCI22475Lessel, D., Ozel, A. B., Campbell, S. E., Saadi, A., Arlt, M. F., McSweeney, K. M., Plaiasu, V., Szakszon, K., Szőllős, A., Rusu, C., Rojas, A. J., Lopez-Valdez, J., Thiele, H., Nürnberg, P., Nickerson, D. A., Bamshad, M. J., Li, J. Z., Kubisch, C., Glover, T. W., & Gordon, L. B. (2018). Analyses of LMNA-negative juvenile progeroid cases confirms biallelic POLR3A mutations in Wiedemann-Rautenstrauch-like syndrome and expands the phenotypic spectrum of PYCR1 mutations. Human genetics, 137(11-12), 921–939. https://doi.org/10.1007/s00439-018-1957-1Levi, N., Papismadov, N., Solomonov, I., Sagi, I., & Krizhanovsky, V. (2020). The ECM path of senescence in aging: components and modifiers. The FEBS journal, 287(13), 2636–2646. https://doi.org/10.1111/febs.15282Li, P., Gan, Y., Xu, Y., Song, L., Wang, L., Ouyang, B., Zhang, C., & Zhou, Q. (2017). The inflammatory cytokine TNF-α promotes the premature senescence of rat nucleus pulposus cells via the PI3K/Akt signaling pathway. Scientific reports, 7, 42938. https://doi.org/10.1038/srep42938Lieberman J. (2018). Unveiling the RNA World. The New England journal of medicine, 379(13), 1278–1280. https://doi.org/10.1056/NEJMcibr1808725López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2013). The hallmarks of aging. Cell, 153(6), 1194–1217. https://doi.org/10.1016/j.cell.2013.05.039López-Otín, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186(2), 243–278. https://doi.org/10.1016/j.cell.2022.11.001Majewski, J., Schwartzentruber, J., Lalonde, E., Montpetit, A., & Jabado, N. (2011). What can exome sequencing do for you?. Journal of medical genetics, 48(9), 580–589. https://doi.org/10.1136/jmedgenet-2011-100223Martin G. M. (1982). Syndromes of accelerated aging. National Cancer Institute monograph, 60, 241–247.Martin G. M. (2005). Genetic modulation of senescent phenotypes in Homo sapiens. Cell, 120(4), 523–532. https://doi.org/10.1016/j.cell.2005.01.031Mathon, N. F., Malcolm, D. S., Harrisingh, M. C., Cheng, L., & Lloyd, A. C. (2001). Lack of replicative senescence in normal rodent glia. Science (New York, N.Y.), 291(5505), 872–875. https://doi.org/10.1126/science.1056782Morales, L. C., Arboleda, G., Rodríguez, Y., Forero, D. A., Ramírez, N., Yunis, J. J., & Arboleda, H. (2009). Absence of Lamin A/C gene mutations in four Wiedemann-Rautenstrauch syndrome patients. American journal of medical genetics. Part A, 149A(12), 2695–2699. https://doi.org/10.1002/ajmg.a.33090Mukherjee, S., Date, A., Patravale, V., Korting, H. C., Roeder, A., & Weindl, G. (2006). Retinoids in the treatment of skin aging: an overview of clinical efficacy and safety. Clinical interventions in aging, 1(4), 327–348. https://doi.org/10.2147/ciia.2006.1.4.327Nunes, V. S., & Moretti, N. S. (2017). Nuclear subcompartments: an overview. Cell biology international, 41(1), 2–7. https://doi.org/10.1002/cbin.10703Ovadya, Y., & Krizhanovsky, V. (2014). Senescent cells: SASPected drivers of age-related pathologies. Biogerontology, 15(6), 627–642. https://doi.org/10.1007/s10522-014-9529-9Paolacci, S., Bertola, D., Franco, J., Mohammed, S., Tartaglia, M., Wollnik, B., & Hennekam, R. C. (2017). Wiedemann-Rautenstrauch syndrome: A phenotype analysis. American journal of medical genetics. Part A, 173(7), 1763–1772. https://doi.org/10.1002/ajmg.a.38246Paolacci, S., Li, Y., Agolini, E., Bellacchio, E., Arboleda-Bustos, C. E., Carrero, D., Bertola, D., Al-Gazali, L., Alders, M., Altmüller, J., Arboleda, G., Beleggia, F., Bruselles, A., Ciolfi, A., Gillessen-Kaesbach, G., Krieg, T., Mohammed, S., Müller, C., Novelli, A., Ortega, J., … Hennekam, R. C. (2018). Specific combinations of biallelic POLR3A variants cause Wiedemann-Rautenstrauch syndrome. Journal of medical genetics, 55(12), 837–846. https://doi.org/10.1136/jmedgenet-2018-105528Partridge, L., & Gems, D. (2002). Mechanisms of ageing: public or private?. Nature reviews. Genetics, 3(3), 165–175. https://doi.org/10.1038/nrg753Pivnick, E. K., Angle, B., Kaufman, R. A., Hall, B. D., Pitukcheewanont, P., Hersh, J. H., Fowlkes, J. L., Sanders, L. P., O'Brien, J. M., Carroll, G. S., Gunther, W. M., Morrow, H. G., Burghen, G. A., & Ward, J. C. (2000). Neonatal progeroid (Wiedemann-Rautenstrauch) syndrome: report of five new cases and review. American journal of medical genetics, 90(2), 131–140.Plotnikov, A., Zehorai, E., Procaccia, S., & Seger, R. (2011). The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation. Biochimica et biophysica acta, 1813(9), 1619–1633. https://doi.org/10.1016/j.bbamcr.2010.12.012Puzianowska-Kuznicka, M., & Kuznicki, J. (2005). Genetic alterations in accelerated ageing syndromes. Do they play a role in natural ageing?. The international journal of biochemistry & cell biology, 37(5), 947–960. https://doi.org/10.1016/j.biocel.2004.10.011Rautenstrauch, T., & Snigula, F. (1977). Progeria: A cell culture study and clinical report of familial incidence. European Journal of Pediatrics, 124(2), 101– 111. https://doi.org/10.1007/BF00477545Rautenstrauch, T., Snigula, F., & Wiedemann, H. R. (1994). Neonatales progeroides Syndrom (Wiedemann-Rautenstrauch). Eine follow-up-Studie [Neonatal progeroid syndrome (Wiedemann-Rautenstrauch). A follow-up study]. Klinische Padiatrie, 206(6), 440–443. https://doi.org/10.1055/s-2008-1046647Ressler, S., Bartkova, J., Niederegger, H., Bartek, J., Scharffetter-Kochanek, K., Jansen-Dürr, P., & Wlaschek, M. (2006). p16INK4A is a robust in vivo biomarker of cellular aging in human skin. Aging cell, 5(5), 379–389. https://doi.org/10.1111/j.1474-9726.2006.00231.xRicklefs R. E. (1998). Evolutionary theories of aging: confirmation of a fundamental prediction, with implications for the genetic basis and evolution of life span. The American naturalist, 152(1), 24–44. https://doi.org/10.1086/286147Romá-Mateo, C., Seco-Cervera, M., Ibáñez-Cabellos, J. S., Pérez, G., Berenguer-Pascual, E., Rodríguez, L. R., & García-Giménez, J. L. (2018). Oxidative Stress and the Epigenetics of Cell Senescence: Insights from Progeroid Syndromes. Current pharmaceutical design, 24(40), 4755–4770. https://doi.org/10.2174/1381612824666190114164117Saitsu, H., Osaka, H., Sasaki, M., Takanashi, J., Hamada, K., Yamashita, A., Shibayama, H., Shiina, M., Kondo, Y., Nishiyama, K., Tsurusaki, Y., Miyake, N., Doi, H., Ogata, K., Inoue, K., & Matsumoto, N. (2011). Mutations in POLR3A and POLR3B encoding RNA Polymerase III subunits cause an autosomal-recessive hypomyelinating leukoencephalopathy. American journal of human genetics, 89(5), 644–651. https://doi.org/10.1016/j.ajhg.2011.10.003Scaffidi, P., & Misteli, T. (2006). Lamin A-dependent nuclear defects in human aging. Science (New York, N.Y.), 312(5776), 1059–1063. https://doi.org/10.1126/science.1127168Shalem, O., Sanjana, N. E., Hartenian, E., Shi, X., Scott, D. A., Mikkelson, T., Heckl, D., Ebert, B. L., Root, D. E., Doench, J. G., & Zhang, F. (2014). Genome-scale CRISPR-Cas9 knockout screening in human cells. Science (New York, N.Y.), 343(6166), 84–87. https://doi.org/10.1126/science.1247005Sherr, C. J., & DePinho, R. A. (2000). Cellular senescence: mitotic clock or culture shock?. Cell, 102(4), 407–410. https://doi.org/10.1016/s0092-8674(00)00046-5Shimojima, K., Shimada, S., Tamasaki, A., Akaboshi, S., Komoike, Y., Saito, A., Furukawa, T., & Yamamoto, T. (2014). Novel compound heterozygous mutations of POLR3A revealed by whole-exome sequencing in a patient with hypomyelination. Brain & development, 36(4), 315–321. https://doi.org/10.1016/j.braindev.2013.04.011Sinclair, D. A., & Guarente, L. (1997). Extrachromosomal rDNA circles--a cause of aging in yeast. Cell, 91(7), 1033–1042. https://doi.org/10.1016/s0092-8674(00)80493-6Thiffault, I., Wolf, N. I., Forget, D., Guerrero, K., Tran, L. T., Choquet, K., Lavallée-Adam, M., Poitras, C., Brais, B., Yoon, G., Sztriha, L., Webster, R. I., Timmann, D., van de Warrenburg, B. P., Seeger, J., Zimmermann, A., Máté, A., Goizet, C., Fung, E., van der Knaap, M. S., Bernard, G. (2015). Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nature communications, 6, 7623. https://doi.org/10.1038/ncomms8623Thorey, F., Jäger, M., Seller, K., Krauspe, R., & Wild, A. (2003). Kyphoskoliose beim Wiedemann-Rautenstrauch-Syndrom (neonatales Progerie Syndrom) [Kyphoscoliosis in Wiedemann-Rautenstrauch-syndrome (neonatal progeroid syndrome)]. Zeitschrift fur Orthopadie und ihre Grenzgebiete, 141(3), 341–344. https://doi.org/10.1055/s-2003-40084Tiku, V., & Antebi, A. (2018). Nucleolar Function in Lifespan Regulation. Trends in cell biology, 28(8), 662–672. https://doi.org/10.1016/j.tcb.2018.03.007Timmers, P. R. H. J., Tiys, E. S., Sakaue, S., Akiyama, M., Kiiskinen, T. T. J., Zhou, W., Hwang, S. J., Yao, C., Biobank Japan Project, FinnGen, Deelen, J., Levy, D., Ganna, A., Kamatani, Y., Okada, Y., Joshi, P. K., Wilson, J. F., & Tsepilov, Y. A. (2022). Mendelian randomization of genetically independent aging phenotypes identifies LPA and VCAM1 as biological targets for human aging. Nature aging, 2(1), 19–30. https://doi.org/10.1038/s43587-021-00159-8Troen B. R. (2003). The biology of aging. The Mount Sinai journal of medicine, New York, 70(1), 3–22.Turowski, T. W., & Tollervey, D. (2016). Transcription by RNA polymerase III: insights into mechanism and regulation. Biochemical Society transactions, 44(5), 1367–1375. https://doi.org/10.1042/BST20160062Ungewitter, E., & Scrable, H. (2009). Antagonistic pleiotropy and p53. Mechanisms of ageing and development, 130(1-2), 10–17. https://doi.org/10.1016/j.mad.2008.06.002Varani, J., Warner, R. L., Gharaee-Kermani, M., Phan, S. H., Kang, S., Chung, J. H., Wang, Z. Q., Datta, S. C., Fisher, G. J., & Voorhees, J. J. (2000). Vitamin A antagonizes decreased cell growth and elevated collagen-degrading matrix metalloproteinases and stimulates collagen accumulation in naturally aged human skin. The Journal of investigative dermatology, 114(3), 480–486. https://doi.org/10.1046/j.1523-1747.2000.00902.xVelasquez-Mendez K. (2019). Analysis of POLR3A gene expression in fibroblasts from Wiedemann-Rautenstrauch Syndrome patients. Autonomous University of Barcelona.Vitale, G., Salvioli, S., & Franceschi, C. (2013). Oxidative stress and the ageing endocrine system. Nature reviews. Endocrinology, 9(4), 228–240. https://doi.org/10.1038/nrendo.2013.29Wang, M., & Lemos, B. (2019). Ribosomal DNA harbors an evolutionarily conserved clock of biological aging. Genome research, 29(3), 325–333. https://doi.org/10.1101/gr.241745.118Wang, Z., Gerstein, M., & Snyder, M. (2009). RNA-Seq: a revolutionary tool for transcriptomics. Nature reviews. Genetics, 10(1), 57–63. https://doi.org/10.1038/nrg2484Wang, T., Wei, J. J., Sabatini, D. M., & Lander, E. S. (2014). Genetic screens in human cells using the CRISPR-Cas9 system. Science (New York, N.Y.), 343(6166), 80–84. https://doi.org/10.1126/science.1246981Warner, H. R., & Sierra, F. (2003). Models of accelerated ageing can be informative about the molecular mechanisms of ageing and/or age-related pathology. Mechanisms of ageing and development, 124(5), 581–587. https://doi.org/10.1016/s0047-6374(03)00008-3Warrenburg, B. P., Seeger, J., Zimmermann, A., Máté, A., Goizet, C., Fung, E., van der Knaap, M. S., … Bernard, G. (2015). Recessive mutations in POLR1C cause a leukodystrophy by impairing biogenesis of RNA polymerase III. Nature communications, 6, 7623. https://doi.org/10.1038/ncomms8623Wiedemann H. R. (1979). An unidentified neonatal progeroid syndrome: follow-up report. European journal of pediatrics, 130(1), 65–70. https://doi.org/10.1007/BF00441901Wolf, N. I., Vanderver, A., van Spaendonk, R. M., Schiffmann, R., Brais, B., Bugiani, M., Sistermans, E., Catsman-Berrevoets, C., Kros, J. M., Pinto, P. S., Pohl, D., Tirupathi, S., Strømme, P., de Grauw, T., Fribourg, S., Demos, M., Pizzino, A., Naidu, S., Guerrero, K., van der Knaap, M. S., … 4H Research Group (2014). Clinical spectrum of 4H leukodystrophy caused by POLR3A and POLR3B mutations. Neurology, 83(21), 1898–1905. https://doi.org/10.1212/WNL.0000000000001002Xu, Y., Li, N., Xiang, R., & Sun, P. (2014). Emerging roles of the p38 MAPK and PI3K/AKT/mTOR pathways in oncogene-induced senescence. Trends in biochemical sciences, 39(6), 268–276. https://doi.org/10.1016/j.tibs.2014.04.004Yosef, R., Pilpel, N., Papismadov, N., Gal, H., Ovadya, Y., Vadai, E., Miller, S., Porat, Z., Ben-Dor, S., & Krizhanovsky, V. (2017). p21 maintains senescent cell viability under persistent DNA damage response by restraining JNK and caspase signaling. The EMBO journal, 36(15), 2280–2295. https://doi.org/10.15252/embj.201695553Yousef, H., Czupalla, C. J., Lee, D., Chen, M. B., Burke, A. N., Zera, K. A., Zandstra, J., Berber, E., Lehallier, B., Mathur, V., Nair, R. V., Bonanno, L. N., Yang, A. C., Peterson, T., Hadeiba, H., Merkel, T., Körbelin, J., Schwaninger, M., Buckwalter, M. S., Quake, S. R., … Wyss-Coray, T. (2019). Aged blood impairs hippocampal neural precursor activity and activates microglia via brain endothelial cell VCAM1. Nature medicine, 25(6), 988–1000. https://doi.org/10.1038/s41591-019-0440-4Zarei, A., Razban, V., Hosseini, S. E., & Tabei, S. M. B. (2019). Creating cell and animal models of human disease by genome editing using CRISPR/Cas9. The journal of gene medicine, 21(4), e3082. https://doi.org/10.1002/jgm.3082Análisis funcional celular/molecular de la RNA polimerasa III A (POLR3A) asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)Ministerio de Ciencia, Tecnología e InnovaciónEstudiantesInvestigadoresMaestrosLICENSElicense.txtlicense.txttext/plain; charset=utf-85879https://repositorio.unal.edu.co/bitstream/unal/84852/1/license.txteb34b1cf90b7e1103fc9dfd26be24b4aMD51ORIGINAL1022422573.2023.pdf1022422573.2023.pdfTesis de Maestría en Ciencias - Bioquímicaapplication/pdf14602664https://repositorio.unal.edu.co/bitstream/unal/84852/2/1022422573.2023.pdffee38f70523f555ab68d85dd06f2138bMD52THUMBNAIL1022422573.2023.pdf.jpg1022422573.2023.pdf.jpgGenerated Thumbnailimage/jpeg5505https://repositorio.unal.edu.co/bitstream/unal/84852/3/1022422573.2023.pdf.jpg27e04476f5aecab0fa8070555ca12eb2MD53unal/84852oai:repositorio.unal.edu.co:unal/848522023-10-30 23:13:00.612Repositorio Institucional Universidad 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

Estudio Celular y Molecular del Gen POLR3A asociado al Síndrome Progeroide Neonatal (Síndrome de Wiedemann-Rautenstrauch)

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