title: Expression of the genetic suppressor element 24.2 (GSE24.2) decreases DNA damage and oxidative stress in X-linked dyskeratosis congenita cells.
abstract: The predominant X-linked form of Dyskeratosis congenita results from mutations in DKC1, which encodes dyskerin, a protein required for ribosomal RNA modification that is also a component of the telomerase complex. We have previously found that expression of an internal fragment of dyskerin (GSE24.2) rescues telomerase activity in X-linked dyskeratosis congenita (X-DC) patient cells. Here we have found that an increased basal and induced DNA damage response occurred in X-DC cells in comparison with normal cells. DNA damage that is also localized in telomeres results in increased heterochromatin formation and senescence. Expression of a cDNA coding for GSE24.2 rescues both global and telomeric DNA damage. Furthermore, transfection of bacterial purified or a chemically synthesized GSE24.2 peptide is able to rescue basal DNA damage in X-DC cells. We have also observed an increase in oxidative stress in X-DC cells and expression of GSE24.2 was able to diminish it. Altogether our data indicated that supplying GSE24.2, either from a cDNA vector or as a peptide reduces the pathogenic effects of Dkc1 mutations and suggests a novel therapeutic approach.
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain; CIBER de Enfermedades Raras, Valencia, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Manguan-Garcia
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Pintado-Berninches
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.
authors.forename: Jaime
authors.initials: J
authors.lastname: Carrillo
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain; CIBER de Enfermedades Raras, Valencia, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Machado-Pinilla
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain; CIBER de Enfermedades Raras, Valencia, Spain.
authors.forename: Leandro
authors.initials: L
authors.lastname: Sastre
authors.affiliation: Biomedical Research Institute INCLIVA, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.
authors.forename: Carme
authors.initials: C
authors.lastname: Pérez-Quilis
authors.affiliation: Biomedical Research Institute INCLIVA, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.
authors.forename: Isabel
authors.initials: I
authors.lastname: Esmoris
authors.affiliation: Biomedical Research Institute INCLIVA, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.
authors.forename: Amparo
authors.initials: A
authors.lastname: Gimeno
authors.affiliation: CIBER de Enfermedades Raras, Valencia, Spain; Biomedical Research Institute INCLIVA, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.
authors.forename: Jose Luis
authors.initials: JL
authors.lastname: García-Giménez
authors.affiliation: CIBER de Enfermedades Raras, Valencia, Spain; Biomedical Research Institute INCLIVA, Valencia, Spain; Department of Physiology, Faculty of Medicine and Dentistry, University of Valencia, Valencia, Spain.
authors.forename: Federico V
authors.initials: FV
authors.lastname: Pallardó
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain; CIBER de Enfermedades Raras, Valencia, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Perona
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins / Q000235:genetics*; D002460:Cell Line; D004249:DNA Damage; D019871:Dyskeratosis Congenita / Q000235:genetics* / Q000378:metabolism / Q000473:pathology / Q000628:therapy; D005786:Gene Expression Regulation; D015316:Genetic Therapy; D006570:Heterochromatin / Q000235:genetics / Q000473:pathology; D006801:Humans; D051379:Mice; D009687:Nuclear Proteins / Q000235:genetics*; D018384:Oxidative Stress; D010455:Peptides / Q000235:genetics / Q000627:therapeutic use; D016615:Telomere / Q000235:genetics / Q000473:pathology; D014162:Transfection
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; D006570:Heterochromatin; D009687:Nuclear Proteins; D010455:Peptides