{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,6,2]],"date-time":"2025-06-02T12:27:47Z","timestamp":1748867267032,"version":"3.37.3"},"reference-count":59,"publisher":"Oxford University Press (OUP)","issue":"9","license":[{"start":{"date-parts":[[2024,2,4]],"date-time":"2024-02-04T00:00:00Z","timestamp":1707004800000},"content-version":"vor","delay-in-days":1,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III"},{"name":"European Regional Development","award":["PI20-00335"],"award-info":[{"award-number":["PI20-00335"]}]},{"name":"Consejo Superior de Investigaciones Cientificas, Spain","award":["PIE-202180E073"],"award-info":[{"award-number":["PIE-202180E073"]}]},{"DOI":"10.13039\/501100002704","name":"Fundaci\u00f3n Cient\u00edfica Asociaci\u00f3n Espa\u00f1ola Contra el Cancer","doi-asserted-by":"crossref","award":["POSTD20042BENI"],"award-info":[{"award-number":["POSTD20042BENI"]}],"id":[{"id":"10.13039\/501100002704","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,4,18]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Telomeres are nucleoprotein structures at the end of chromosomes that maintain their integrity. Mutations in genes coding for proteins involved in telomere protection and elongation produce diseases such as dyskeratosis congenita or idiopathic pulmonary fibrosis known as telomeropathies. These diseases are characterized by premature telomere shortening, increased DNA damage and oxidative stress. Genetic diagnosis of telomeropathy patients has identified mutations in the genes TERT and TERC coding for telomerase components but the functional consequences of many of these mutations still have to be experimentally demonstrated. The activity of twelve TERT and five TERC mutants, five of them identified in Spanish patients, has been analyzed. TERT and TERC mutants were expressed in VA-13 human cells that express low telomerase levels and the activity induced was analyzed. The production of reactive oxygen species, DNA oxidation and TRF2 association at telomeres, DNA damage response and cell apoptosis were determined. Most mutations presented decreased telomerase activity, as compared to wild-type TERT and TERC. In addition, the expression of several TERT and TERC mutants induced oxidative stress, DNA oxidation, DNA damage, decreased recruitment of the shelterin component TRF2 to telomeres and increased apoptosis. These observations might indicate that the increase in DNA damage and oxidative stress observed in cells from telomeropathy patients is dependent on their TERT or TERC mutations. Therefore, analysis of the effect of TERT and TERC mutations of unknown function on DNA damage and oxidative stress could be of great utility to determine the possible pathogenicity of these variants.<\/jats:p>","DOI":"10.1093\/hmg\/ddae015","type":"journal-article","created":{"date-parts":[[2024,4,20]],"date-time":"2024-04-20T00:57:01Z","timestamp":1713574621000},"page":"818-834","source":"Crossref","is-referenced-by-count":2,"title":["Clinical mutations in the <i>TERT<\/i> and <i>TERC<\/i> genes coding for telomerase components induced oxidative stress, DNA damage at telomeres and cell apoptosis besides decreased telomerase activity"],"prefix":"10.1093","volume":"33","author":[{"given":"Beatriz","family":"Fern\u00e1ndez-Varas","sequence":"first","affiliation":[{"name":"Instituto de Investigaciones Biomedicas Sols\/Morreale CSIC\/UAM , Arturo Duperier 4, 28029 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Manguan-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biomedicas Sols\/Morreale CSIC\/UAM , Arturo Duperier 4, 28029 Madrid , Spain"},{"name":"Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) , Instituto de Salud Carlos III. C. Melchor Fernandez de Almagro, 3, 28029 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Javier","family":"Rodriguez-Centeno","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biomedicas Sols\/Morreale CSIC\/UAM , Arturo Duperier 4, 28029 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luc\u00eda","family":"Mendoza-Lupi\u00e1\u00f1ez","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biomedicas Sols\/Morreale CSIC\/UAM , Arturo Duperier 4, 28029 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Joaquin","family":"Calatayud","sequence":"additional","affiliation":[{"name":"Departamento de Biolog\u00eda y Geolog\u00eda , F\u00edsica y Qu\u00edmica inorg\u00e1nica. , C\/Tulip\u00e1n s\/n, M\u00f3stoles, C.P. 28933 Madrid , Spain"},{"name":"ESCET, Universidad Rey Juan Carlos , F\u00edsica y Qu\u00edmica inorg\u00e1nica. , C\/Tulip\u00e1n s\/n, M\u00f3stoles, C.P. 28933 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rosario","family":"Perona","sequence":"additional","affiliation":[{"name":"Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) , Instituto de Salud Carlos III. C. Melchor Fernandez de Almagro, 3, 28029 Madrid , Spain"},{"name":"Instituto de Salud Carlos III. Calle Monforte de Lemos 5 , 28029 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mercedes","family":"Mart\u00edn-Mart\u00ednez","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica CSIC , Juan de la Cierva 3, 28006 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marta","family":"Gutierrez-Rodriguez","sequence":"additional","affiliation":[{"name":"Instituto de Qu\u00edmica M\u00e9dica CSIC , Juan de la Cierva 3, 28006 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlos","family":"Ben\u00edtez-Buelga","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biomedicas Sols\/Morreale CSIC\/UAM , Arturo Duperier 4, 28029 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3613-5938","authenticated-orcid":false,"given":"Leandro","family":"Sastre","sequence":"additional","affiliation":[{"name":"Instituto de Investigaciones Biomedicas Sols\/Morreale CSIC\/UAM , Arturo Duperier 4, 28029 Madrid , Spain"},{"name":"Centro de Investigacion Biomedica en Red de Enfermedades Raras (CIBERER) , Instituto de Salud Carlos III. 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Melchor Fernandez de Almagro, 3, 28029 Madrid , Spain"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"286","published-online":{"date-parts":[[2024,2,3]]},"reference":[{"key":"2024042000563166900_ref1","doi-asserted-by":"crossref","first-page":"306","DOI":"10.1016\/j.cell.2020.12.028","article-title":"Telomeres: history, health, and hallmarks of aging","volume":"184","author":"Chakravarti","year":"2021","journal-title":"Cell"},{"key":"2024042000563166900_ref2","doi-asserted-by":"crossref","first-page":"36","DOI":"10.1038\/s41525-021-00198-5","article-title":"Telomere biology disorders","volume":"6","author":"Kam","year":"2021","journal-title":"NPJ Genom Med"},{"key":"2024042000563166900_ref3","doi-asserted-by":"crossref","first-page":"363","DOI":"10.1146\/annurev-genom-010422-091101","article-title":"The role of telomeres in human disease","volume":"23","author":"Armanios","year":"2022","journal-title":"Annu Rev Genomics Hum 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