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

Abstract

Hypoxia promotes genetic instability for tumor progression. Recent evidence indicates that the transcription factor HIF-1α impairs DNA mismatch repair, yet the role of HIF-1α isoform, HIF-2α, in tumor progression remains obscure. In pursuit of the involvement of HIF-α in chromosomal instability, we report here that HIF-1α, 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-2α fails to do so. We demonstrate that this functional distinction stems from phosphorylation of HIF-2α 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-1α from HIF-2α, and arguing a unique role for HIF-1α in tumor progression by promoting genomic instability. © 2006 European Molecular Biology Organization | All Rights Reserved.