The Werner syndrome gene product (WRN): a repressor of hypoxia-inducible factor-1 activity

Exp Cell Res. 2012 Aug 15;318(14):1620-32. doi: 10.1016/j.yexcr.2012.04.010. Epub 2012 May 31.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Cells, Cultured
  • Exodeoxyribonucleases / genetics
  • Exodeoxyribonucleases / metabolism*
  • HeLa Cells
  • Humans
  • Mitochondria / metabolism
  • Neoplasm Proteins / metabolism*
  • Reactive Oxygen Species / metabolism
  • RecQ Helicases / genetics
  • RecQ Helicases / metabolism*
  • Werner Syndrome / genetics*
  • Werner Syndrome Helicase

Substances

  • HIG1 protein, human
  • Neoplasm Proteins
  • Reactive Oxygen Species
  • Exodeoxyribonucleases
  • RecQ Helicases
  • WRN protein, human
  • Werner Syndrome Helicase