Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity

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 dyskeratos is congenita oridiopathic pulmonary fibrosis known as telomeropathies. These disea...

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Autores: Fernández-Varas, Beatriz, Manguan-García, Cristina, Rodriguez-Centeno, Javier, Mendoza-Lupiáñez, Lucía, Calatayud, Joaquín, Perona Abellón, Rosario, Gutiérrez-Rodríguez, Marta, Benitez-Buelga, Carlos, Sastre, Leandro
Tipo de recurso: artículo
Estado:Versión publicada
Fecha de publicación:2024
País:España
Institución:Consejo Superior de Investigaciones Científicas (CSIC)
Repositorio:DIGITAL.CSIC. Repositorio Institucional del CSIC
OAI Identifier:oai:digital.csic.es:10261/359595
Acceso en línea:http://hdl.handle.net/10261/359595
Access Level:acceso abierto
Palabra clave:TERT/TERC
DNA damage
oxidative stress
apoptosis
telomeropathies
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spelling Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activityFernández-Varas, BeatrizManguan-García, CristinaRodriguez-Centeno, JavierMendoza-Lupiáñez, LucíaCalatayud, JoaquínPerona Abellón, RosarioGutiérrez-Rodríguez, MartaBenitez-Buelga, CarlosSastre, LeandroTERT/TERCDNA damageoxidative stressapoptosistelomeropathiesTelomeres 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 dyskeratos is congenita oridiopathic 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 migh tindicate that the increase in DN Adamage 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.This work was supported by Fondo de Investigaciones Sanitarias, Instituto de Salud Carlos III, Spain, co-funded by European Regional Development (FEDER) funds [grant number PI20-00335] and Consejo Superior de Investigaciones Cientificas, Spain [grant PIE-202180E073]. BF-V was funded by a contract from Comunidad Autonoma deMadrid and the Fondo Social Europeo as part of the iniciativa de Empleo Juvenil (YEI), Spain. CB-B was funded by a postdoctoral contract from the Fundación Científica Asociación Española Contra el Cancer (AECC) [POSTD20042BENI].Oxford University PressInstituto de Salud Carlos IIIEuropean CommissionConsejo Superior de Investigaciones Científicas (España)Comunidad de MadridFundación Científica Asociación Española Contra el CáncerConsejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]2024202420242024info:eu-repo/semantics/articlehttp://purl.org/coar/resource_type/c_6501Publisher's versioninfo:eu-repo/semantics/publishedVersionhttp://hdl.handle.net/10261/359595reponame:DIGITAL.CSIC. Repositorio Institucional del CSICinstname:Consejo Superior de Investigaciones Científicas (CSIC)Ingléshttp://dx.doi.org/10.1093/hmg/ddae015Síinfo:eu-repo/semantics/openAccessoai:digital.csic.es:10261/3595952026-05-22T06:33:51Z
dc.title.none.fl_str_mv Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
title Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
spellingShingle Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
Fernández-Varas, Beatriz
TERT/TERC
DNA damage
oxidative stress
apoptosis
telomeropathies
title_short Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
title_full Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
title_fullStr Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
title_full_unstemmed Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
title_sort Clinical mutations in the TERT and TERC genes coding for telomerase components induced oxidative stress, DNAdamage at telomeres and cell apoptosis besides decreased telomerase activity
dc.creator.none.fl_str_mv Fernández-Varas, Beatriz
Manguan-García, Cristina
Rodriguez-Centeno, Javier
Mendoza-Lupiáñez, Lucía
Calatayud, Joaquín
Perona Abellón, Rosario
Gutiérrez-Rodríguez, Marta
Benitez-Buelga, Carlos
Sastre, Leandro
author Fernández-Varas, Beatriz
author_facet Fernández-Varas, Beatriz
Manguan-García, Cristina
Rodriguez-Centeno, Javier
Mendoza-Lupiáñez, Lucía
Calatayud, Joaquín
Perona Abellón, Rosario
Gutiérrez-Rodríguez, Marta
Benitez-Buelga, Carlos
Sastre, Leandro
author_role author
author2 Manguan-García, Cristina
Rodriguez-Centeno, Javier
Mendoza-Lupiáñez, Lucía
Calatayud, Joaquín
Perona Abellón, Rosario
Gutiérrez-Rodríguez, Marta
Benitez-Buelga, Carlos
Sastre, Leandro
author2_role author
author
author
author
author
author
author
author
dc.contributor.none.fl_str_mv Instituto de Salud Carlos III
European Commission
Consejo Superior de Investigaciones Científicas (España)
Comunidad de Madrid
Fundación Científica Asociación Española Contra el Cáncer
Consejo Superior de Investigaciones Científicas [https://ror.org/02gfc7t72]
dc.subject.none.fl_str_mv TERT/TERC
DNA damage
oxidative stress
apoptosis
telomeropathies
topic TERT/TERC
DNA damage
oxidative stress
apoptosis
telomeropathies
description 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 dyskeratos is congenita oridiopathic 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 migh tindicate that the increase in DN Adamage 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.
publishDate 2024
dc.date.none.fl_str_mv 2024
2024
2024
2024
dc.type.none.fl_str_mv info:eu-repo/semantics/article
http://purl.org/coar/resource_type/c_6501
Publisher's version
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv http://hdl.handle.net/10261/359595
url http://hdl.handle.net/10261/359595
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv http://dx.doi.org/10.1093/hmg/ddae015
Sí
dc.rights.none.fl_str_mv info:eu-repo/semantics/openAccess
eu_rights_str_mv openAccess
dc.publisher.none.fl_str_mv Oxford University Press
publisher.none.fl_str_mv Oxford University Press
dc.source.none.fl_str_mv reponame:DIGITAL.CSIC. Repositorio Institucional del CSIC
instname:Consejo Superior de Investigaciones Científicas (CSIC)
instname_str Consejo Superior de Investigaciones Científicas (CSIC)
reponame_str DIGITAL.CSIC. Repositorio Institucional del CSIC
collection DIGITAL.CSIC. Repositorio Institucional del CSIC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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