1. A dyskerin motif reactivates telomerase activity in X-linked dyskeratosis congenita and in telomerase-deficient human cells.
- Author
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Machado-Pinilla R, Sánchez-Pérez I, Murguía JR, Sastre L, and Perona R
- Subjects
- Amino Acid Sequence, Animals, Cell Line, Cell Survival drug effects, Cisplatin pharmacology, Drug Resistance drug effects, Enzyme Activation drug effects, Enzyme Inhibitors pharmacology, Humans, Mice, Molecular Sequence Data, Promoter Regions, Genetic, Protein Structure, Tertiary, Proto-Oncogene Proteins c-myc genetics, RNA metabolism, Structure-Activity Relationship, Telomerase antagonists & inhibitors, Amino Acid Motifs, Cell Cycle Proteins chemistry, Dyskeratosis Congenita enzymology, Nuclear Proteins chemistry, Peptide Fragments chemistry, Telomerase deficiency, Telomerase metabolism
- Abstract
Dyskerin gene is mutated in patients with X-linked dyskeratosis congenita (X-DC), which results in greatly reduced levels of telomerase activity. A genetic suppressor element (GSE) termed GSE24-2 has been isolated in a screening for cisplatin resistance. GSE24-2-expressing cells presented impaired telomerase inhibition following in vitro exposure to chemotherapies, such as cisplatin, or telomerase inhibitors. The promoter of the telomerase component hTERT was constitutively activated in GSE24-2 cells in a c-myc expression-dependent manner. Deletion analyses and mutagenesis of the human c-myc promoter demonstrated that the target sequence for activation was the nuclease hypersensitive element-III (NHEIII) site located upstream to the P1 region of the promoter. Further, expression of GSE24-2 in cell lines derived from patients with X-DC and in VA13 cells induced increased hTERT RNA and hTR levels and recovery of telomerase activity. Finally, expression of GSE24-2 was able to rescue X-DC fibroblasts from premature senescence. These data demonstrate that this domain of dyskerin plays an important role in telomerase maintenance following cell insults such as cisplatin treatment, and in telomerase-defective cells in patients with X-DC. The expression of this dyskerin fragment has a dominant function in X-DC cells and could provide the basis for a therapeutic approach to this disease.
- Published
- 2008
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