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.

Molecular Diagnosis and Precision Therapeutic Approaches for Telomere Biology Disorders

“…Subsequent studies demonstrated that a shorter fragment of GSE24.2, named GSE4, maintained the same biological activity and induced telomerase activity and cell proliferation of DKC-mutant cells. In addition, DNA damage, oxidative stress and cell senescence were reduced upon expression of GSE4 [201]. GSE24.2 could be delivered to cells using surface modified biodegradable polymeric nanoparticles, which might facilitate their administration to patients [202].…”

Telomere-Related Gene Mutations and Lung Diseases: Pulmonary Fibrosis, Emphysema and Lung Cancer

“…Expression of GSE24.2 decreased both DNA damage and oxidative stress of dyskerin mutant cells 114 . Subsequent studies demonstrated that a shorter fragment of GSE24.2, named GSE4, maintained the same biological activity and induced telomerase activity and cell proliferation of DKC-mutant cells, decreased DNA damage, oxidative stress and cell senescence 115 . GSE24.2 and GSE4 could be delivered to cells using surface modified biodegradable polymeric nanoparticles, which might facilitate their administration to patients 116 .…”

Aspectos clínicos, etiológicos y terapéuticos de la disqueratosis congénita

“…Entre ellos, la expresión de un péptido derivado de la disquerina, un elemento supresor genético 24.2 (GSE24.2, por sus siglas en inglés), el cual aumenta la actividad de la telomerasa, reduce los efectos patogénicos de las mutaciones Dkc1, disminuye el daño al ADN y el estrés oxidativo, por lo que sugiere un nuevo enfoque terapéutico. Igualmente, la expresión de GSE4, activa los promotores de c-myc y TERT, además aumento la expresión de cmyc, TERT y TERC (12)(13)(14).…”