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Werner syndrome (WS) is a rare autosomal disease characterized by the premature onset of several age-associated pathologies. The protein defective in WS patients (WRN) is a helicase/exonuclease involved in DNA repair, replication, transcription and telomere maintenance. Hypoxia-inducible factor-1 (HIF-1) is a decisive element for the transcriptional regulation of genes essential for adaptation to low oxygen conditions. HIF-1 is also implicated in the molecular mechanisms of ageing. Here, we show that the cellular depletion of WRN protein (by siRNA targeting) leads to increased HIF-1 complex stabilization and activation. HIF-1 activation in the absence of WRN involves the generation of mitochondrial reactive oxygen species (mtROS) since SkQ1, a mitochondrial-targeted antioxidant, and stigmatellin, an inhibitor of mitochondrial complex III, blocked increased HIF-1 levels. Ascorbate, an essential co-factor involved in HIF-1 stability, was decreased in WRN-depleted cells. Interestingly, expression levels of GLUT1, a known dehydroascorbic acid transporter, were also decreased in WRN-depleted cells. Ascorbate supplementation of WRN-depleted cells led to a dose-dependent inhibition of HIF-1 activation. These results indicate that WRN protein regulates HIF-1 activation by affecting mitochondrial ROS production and intracellular ascorbate levels. This work provides a novel mechanistic link between HIF-1 activity and different age-associated pathologies.

Original publication

DOI

10.1016/j.yexcr.2012.04.010

Type

Journal article

Journal

Experimental cell research

Publication Date

08/2012

Volume

318

Pages

1620 - 1632

Addresses

Centre de Recherche en Cancérologie de l'Université Laval, Centre de recherche du CHUQ, L'Hôtel-Dieu de Québec, Québec, QC, Canada G1R 2J6.

Keywords

Cells, Cultured, Hela Cells, Mitochondria, Humans, Werner Syndrome, Reactive Oxygen Species, Exodeoxyribonucleases, Neoplasm Proteins, RecQ Helicases, Werner Syndrome Helicase