The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression

EMBO J. 2006 Oct 18;25(20):4784-94. doi: 10.1038/sj.emboj.7601369. Epub 2006 Oct 5.

Abstract

Hypoxia promotes genetic instability for tumor progression. Recent evidence indicates that the transcription factor HIF-1alpha impairs DNA mismatch repair, yet the role of HIF-1alpha isoform, HIF-2alpha, in tumor progression remains obscure. In pursuit of the involvement of HIF-alpha in chromosomal instability, we report here that HIF-1alpha, specifically its PAS-B, induces DNA double-strand breaks at least in part by repressing the expression of NBS1, a crucial DNA repair gene constituting the MRE11A-RAD50-NBS1 complex. Despite strong similarities between the two isoforms, HIF-2alpha fails to do so. We demonstrate that this functional distinction stems from phosphorylation of HIF-2alpha Thr-324 by protein kinase D1, which discriminates between subtle differences of the two PAS-B in amino-acid sequence, thereby precluding NBS1 repression. Hence, our findings delineate a molecular pathway that functionally distinguishes HIF-1alpha from HIF-2alpha, and arguing a unique role for HIF-1alpha in tumor progression by promoting genomic instability.

Publication types

  • Research Support, N.I.H., Intramural

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / genetics
  • Basic Helix-Loop-Helix Transcription Factors / metabolism*
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism*
  • Cell Line
  • Chromosomal Instability* / genetics
  • DNA Repair / genetics
  • Down-Regulation / genetics
  • Gene Expression Regulation, Neoplastic* / genetics
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics
  • Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism
  • Neoplasm Proteins / genetics
  • Neoplasm Proteins / metabolism*
  • Neoplasms / genetics
  • Neoplasms / metabolism*
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism*
  • Phosphorylation
  • Protein Processing, Post-Translational
  • Protein Structure, Tertiary / genetics
  • Rabbits

Substances

  • Basic Helix-Loop-Helix Transcription Factors
  • Cell Cycle Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Multiprotein Complexes
  • NBN protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • endothelial PAS domain-containing protein 1