The phosphorylation status of PAS-B distinguishes HIF-1alpha from HIF-2alpha in NBS1 repression.
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.
To
Kenneth K-W
KK
Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Sedelnikova
Olga A
OA
Samons
Melissa
M
Bonner
William M
WM
Huang
L Eric
LE
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D043171:Chromosomal Instability / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D015536:Down-Regulation / Q000235:genetics; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000235:genetics / Q000378:metabolism; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017434:Protein Structure, Tertiary / Q000235:genetics; D011817:Rabbits; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D018797:Cell Cycle Proteins; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D046912:Multiprotein Complexes; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human; C112156:NBN protein, human