Article
- The EMBO Journal (2006) 25, 4784 - 4794
- doi:10.1038/sj.emboj.7601369
Published online: 5 October 2006
Subject Categories:
The phosphorylation status of PAS-B distinguishes HIF-1
from HIF-2 in NBS1 repression
Kenneth K-W To1, Olga A Sedelnikova2, Melissa Samons1, William M Bonner2 and L Eric Huang1,3
- Laboratory of Human Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Laboratory of Molecular Pharmacology, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
- Department of Neurosurgery, University of Utah School of Medicine, Salt Lake City, UT, USA
Correspondence to:
L Eric Huang, Department of Neurosurgery, University of Utah School of Medicine, 30 N 1900 E, Suite 3B409, Salt Lake City, UT 84112, USA. Tel.: +1 801 585 3221; Fax: +1 801 585 7845; E-mail: eric.huang@hsc.utah.edu
Received 21 April 2006; Accepted 29 August 2006
Abstract
Hypoxia promotes genetic instability for tumor progression. Recent evidence indicates that the transcription factor HIF-1
impairs DNA mismatch repair, yet the role of HIF-1 isoform, HIF-2, in tumor progression remains obscure. In pursuit of the involvement of HIF- in chromosomal instability, we report here that HIF-1, 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-2 fails to do so. We demonstrate that this functional distinction stems from phosphorylation of HIF-2 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-1 from HIF-2, and arguing a unique role for HIF-1 in tumor progression by promoting genomic instability.
Keywords:
- double-strand break,
- hypoxia,
- NBS1,
- PAS-B,
- PKD1
