Expression of the genetic suppressor element 24.2 (GSE24.2) decreases DNA damage and oxidative stress in X-linked dyskeratosis congenita cells

• Published in: PloS one Vol. 9; no. 7; p. e101424
• Main Authors: Manguan-Garcia, Cristina, Pintado-Berninches, Laura, Carrillo, Jaime, Machado-Pinilla, Rosario, Sastre, Leandro, Pérez-Quilis, Carme, Esmoris, Isabel, Gimeno, Amparo, García-Giménez, Jose Luis, Pallardó, Federico V, Perona, Rosario
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 02.07.2014; Public Library of Science (PLoS)
• Subjects: Aging; Anemia; Animals; Ataxia; Biology and Life Sciences; Biomedical research; Bone marrow; Cell cycle; Cell Cycle Proteins - genetics; Cell Line; Chromosomes; Damage localization; Dentistry; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; Dyskeratosis; Dyskeratosis Congenita - genetics; Dyskeratosis Congenita - metabolism; Dyskeratosis Congenita - pathology; Dyskeratosis Congenita - therapy; Fibroblasts; Gene expression; Gene Expression Regulation; Genetic suppression; Genetic Therapy; Heterochromatin; Heterochromatin - genetics; Heterochromatin - pathology; Humans; Lipid peroxidation; Medicine; Medicine and Health Sciences; Mice; Mutation; Nuclear Proteins - genetics; Oxidative Stress; Peptides - genetics; Peptides - therapeutic use; Physiology; Proteins; Ribonucleic acid; RNA; RNA modification; rRNA; Senescence; Telomerase; Telomere - genetics; Telomere - pathology; Telomeres; Transfection; Spain
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0101424

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.