1. Expression of the genetic suppressor element 24.2 (GSE24.2) decreases DNA damage and oxidative stress in X-linked dyskeratosis congenita cells.
- Author
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Manguan-Garcia C, Pintado-Berninches L, Carrillo J, Machado-Pinilla R, Sastre L, Pérez-Quilis C, Esmoris I, Gimeno A, García-Giménez JL, Pallardó FV, and Perona R
- Subjects
- Animals, Cell Line, Dyskeratosis Congenita metabolism, Dyskeratosis Congenita pathology, Dyskeratosis Congenita therapy, Genetic Therapy, Heterochromatin genetics, Heterochromatin pathology, Humans, Mice, Peptides genetics, Peptides therapeutic use, Telomere genetics, Telomere pathology, Transfection, Cell Cycle Proteins genetics, DNA Damage, Dyskeratosis Congenita genetics, Gene Expression Regulation, Nuclear Proteins genetics, Oxidative Stress
- 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.
- Published
- 2014
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