Abstract
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.
Publication types
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Research Support, N.I.H., Intramural
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / genetics
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Basic Helix-Loop-Helix Transcription Factors / metabolism*
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line
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Chromosomal Instability* / genetics
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DNA Repair / genetics
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Down-Regulation / genetics
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Gene Expression Regulation, Neoplastic* / genetics
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / genetics
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Hypoxia-Inducible Factor 1, alpha Subunit / metabolism*
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Multiprotein Complexes / genetics
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Multiprotein Complexes / metabolism
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Neoplasm Proteins / genetics
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Neoplasm Proteins / metabolism*
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Neoplasms / genetics
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Neoplasms / metabolism*
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Nuclear Proteins / genetics
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Nuclear Proteins / metabolism*
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Phosphorylation
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Protein Processing, Post-Translational
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Protein Structure, Tertiary / genetics
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Rabbits
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Cell Cycle Proteins
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Multiprotein Complexes
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NBN protein, human
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Neoplasm Proteins
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Nuclear Proteins
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endothelial PAS domain-containing protein 1