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.