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

被引:91
作者
To, Kenneth K. -W
Sedelnikova, Olga A.
Samons, Melissa
Bonner, William M.
Huang, L. Eric
机构
[1] Univ Utah, Sch Med, Dept Neurosurg, Salt Lake City, UT 84112 USA
[2] NCI, Human Carcinogenesis Lab, NIH, Bethesda, MD 20892 USA
[3] NCI, Mol Pharmacol Lab, NIH, Bethesda, MD 20892 USA
关键词
double-strand break; hypoxia; NBS1; PAS-B; PKD1;
D O I
10.1038/sj.emboj.7601369
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Hypoxia promotes genetic instability for tumor progression. Recent evidence indicates that the transcription factor HIF-1 alpha impairs DNA mismatch repair, yet the role of HIF-1 alpha isoform, HIF-2 alpha, in tumor progression remains obscure. In pursuit of the involvement of HIF-alpha in chromosomal instability, we report here that HIF-1 alpha, 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 alpha fails to do so. We demonstrate that this functional distinction stems from phosphorylation of HIF-2 alpha 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 alpha from HIF-2 alpha, and arguing a unique role for HIF-1 alpha in tumor progression by promoting genomic instability.
引用
收藏
页码:4784 / 4794
页数:11
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