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.
Highlights
Telomere maintenance alterations are in the origin of an increasing number of diseases such as dyskeratosis congenita, aplastic anemia or pulmonary fibrosis
The telomerase protein with reverse transcriptase activity is encoded by the TERT gene and uses as template the RNA molecule encoded by the TERC gene that is another component of the telomerase complex [5]
We have previously described that a 55 amino acids-long fragment of the dyskerin TRUB domain, named GSE24.2, has protective effects on cells derived from dyskeratosis congenita patients [18]
Summary
Telomere maintenance alterations are in the origin of an increasing number of diseases such as dyskeratosis congenita, aplastic anemia or pulmonary fibrosis Telomeres are structures located at the end of the chromosomes that play essential roles in chromosome replication and stability [2, 3]. The sequence of their DNA consists of hundreds of repeats of the TTAGGG motif. The DNA replication machinery cannot complete the synthesis of the chromosome ends that is accomplished by a RNA-protein complex with reverse transcriptase activity named telomerase [4]. The telomere DNA binds to a specific protein complex, named shelterin complex, which protects telomeres from degradation [10]. Telomere shortening that occurs during proliferation of non-stem or transformed cells results in genome instability, the fusion of chromosomes and induces apoptotic cell death or senescence [11]
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