Acute telomerase components depletion triggers oxidative stress as an early event previous to telomeric shortening.
Loss of function of dyskerin (DKC1), NOP10 and TIN2 are responsible for different inheritance patterns of Dyskeratosis congenita (DC; ORPHA1775). They are key components of telomerase (DKC1 and NOP10) and shelterin (TIN2), and play an important role in telomere homeostasis. They participate in several fundamental cellular processes by contributing to Dyskeratosis congenita through mechanisms that are not fully understood. Presence of oxidative stress was postulated to result from telomerase ablation. However, the resulting disturbed redox status can promote telomere attrition by generating a vicious circle, which promotes cellular senescence. This fact prompted us to study if acute loss of DKC1, NOP10 and TINF2 can promote redox disequilibrium as an early event when telomere shortening has not yet taken place. We generated siRNA-mediated (DKC1, NOP10 and TINF2) cell lines by RNA interference, which was confirmed by mRNA and protein expression analyses. No telomere shortening occurred in any silenced cell line. Depletion of H/ACA ribonucleoproteins DKC1 and NOP10 diminished telomerase activity via TERC down-regulation, and produced alterations in pseudouridylation and ribosomal biogenesis. An increase in the GSSG/GSH ratio, carbonylated proteins and oxidized peroxiredoxin-6 was observed, in addition to MnSOD and TRX1 overexpression in the siRNA DC cells. Likewise, high PARylation levels and high PARP1 protein expression were detected. In contrast, the silenced TINF2 cells did not alter any evaluated oxidative stress marker. Altogether these findings lead us to conclude that loss of DKC1 and NOP10 functions induces oxidative stress in a telomere shortening independent manner.
['Ibáñez-Cabellos|José Santiago|JS|', 'Pérez-Machado|Giselle|G|', 'Seco-Cervera|Marta|M|', 'Berenguer-Pascual|Ester|E|', 'García-Giménez|José Luis|JL|', 'Pallardó|Federico V|FV|']
D018797:Cell Cycle Proteins D016922:Cellular Senescence D004249:DNA Damage D019871:Dyskeratosis Congenita D006367:HeLa Cells D006801:Humans D009687:Nuclear Proteins D018384:Oxidative Stress D034622:RNA Interference D020718:Ribonucleoproteins, Small Nucleolar D019098:Telomerase D059506:Telomere Shortening D034501:Telomere-Binding Proteins
Oxidative stress Aging Antioxidant DNA damage Telomeropathies