title: GSE4, a Small Dyskerin- and GSE24.2-Related Peptide, Induces Telomerase Activity, Cell Proliferation and Reduces DNA Damage, Oxidative Stress and Cell Senescence in Dyskerin Mutant Cells.
abstract: Dyskeratosis congenita is an inherited disease caused by mutations in genes coding for telomeric components. It was previously reported that expression of a dyskerin-derived peptide, GSE24.2, increases telomerase activity, regulates gene expression and decreases DNA damage and oxidative stress in dyskeratosis congenita patient cells. The biological activity of short peptides derived from GSE24.2 was tested and one of them, GSE4, that probed to be active, was further characterized in this article. Expression of this eleven amino acids long peptide increased telomerase activity and reduced DNA damage, oxidative stress and cell senescence in dyskerin-mutated cells. GSE4 expression also activated c-myc and TERT promoters and increase of c-myc, TERT and TERC expression. The level of biological activity of GSE4 was similar to that obtained by GSE24.2 expression. Incorporation of a dyskerin nuclear localization signal to GSE24.2 did not change its activity on promoter regulation and DNA damage protection. However, incorporation of a signal that increases the rate of nucleolar localization impaired GSE24.2 activity. Incorporation of the dyskerin nuclear localization signal to GSE4 did not alter its biological activity. Mutation of the Aspartic Acid residue that is conserved in the pseudouridine synthase domain present in GSE4 did not impair its activity, except for the repression of c-myc promoter activity and the decrease of c-myc, TERT and TERC gene expression in dyskerin-mutated cells. These results indicated that GSE4 could be of great therapeutic interest for treatment of dyskeratosis congenita patients.
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.|Advanced Medical Projects, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Iarriccio
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.|CIBER de Enfermedades Raras, Valencia, Spain.|IdiPaz, Madrid, Spain.
authors.forename: Cristina
authors.initials: C
authors.lastname: Manguán-García
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Pintado-Berninches
authors.affiliation: Instituto de Química-Física "Rocasolano" CSIC, Madrid, Spain.
authors.forename: José Miguel
authors.initials: JM
authors.lastname: Mancheño
authors.affiliation: Advanced Medical Projects, Madrid, Spain.
authors.forename: Antonio
authors.initials: A
authors.lastname: Molina
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.|CIBER de Enfermedades Raras, Valencia, Spain.|IdiPaz, Madrid, Spain.|Biomarkers and Experimental Therapeutics in Cancer, IdiPaz, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Rosario
authors.initials: R
authors.lastname: Perona
authors.affiliation: Instituto de Investigaciones Biomédicas CSIC/UAM, Madrid, Spain.|CIBER de Enfermedades Raras, Valencia, Spain.|IdiPaz, Madrid, Spain.|Biomarkers and Experimental Therapeutics in Cancer, IdiPaz, Hospital Universitario La Paz, Madrid, Spain.
authors.forename: Leandro
authors.initials: L
authors.lastname: Sastre
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics*; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation; D016922:Cellular Senescence; D004249:DNA Damage; D019871:Dyskeratosis Congenita / Q000235:genetics; D005786:Gene Expression Regulation; D057809:HEK293 Cells; D006801:Humans; D009154:Mutation / Q000235:genetics*; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins / Q000235:genetics*; D018384:Oxidative Stress; D010446:Peptide Fragments; D010455:Peptides / Q000378:metabolism*; D011401:Promoter Regions, Genetic / Q000235:genetics; D019098:Telomerase / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; C112148:DKC1 protein, human; C000603663:GSE24.2 peptide; C000608447:GSE4 peptide, human; D019913:Nuclear Localization Signals; D009687:Nuclear Proteins; D010446:Peptide Fragments; D010455:Peptides; D019098:Telomerase