Hypoxia-inducible factor-1alpha regulates the expression of nucleotide excision repair proteins in keratinocytes.
The regulation of DNA repair enzymes is crucial for cancer prevention, initiation, and therapy. We have studied the effect of ultraviolet B (UVB) radiation on the expression of the two nucleotide excision repair factors (XPC and XPD) in human keratinocytes. We show that hypoxia-inducible factor-1alpha (HIF-1alpha) is involved in the regulation of XPC and XPD. Early UVB-induced downregulation of HIF-1alpha increased XPC mRNA expression due to competition between HIF-1alpha and Sp1 for their overlapping binding sites. Late UVB-induced enhanced phosphorylation of HIF-1alpha protein upregulated XPC mRNA expression by direct binding to a separate hypoxia response element (HRE) in the XPC promoter region. HIF-1alpha also regulated XPD expression by binding to a region of seven overlapping HREs in its promoter. Quantitative chromatin immunoprecipitation assays further revealed putative HREs in the genes encoding other DNA repair proteins (XPB, XPG, CSA and CSB), suggesting that HIF-1alpha is a key regulator of the DNA repair machinery. Analysis of the repair kinetics of 6-4 photoproducts and cyclobutane pyrimidine dimers also revealed that HIF-1alpha downregulation led to an increased rate of immediate removal of both photolesions but attenuated their late removal following UVB irradiation, indicating the functional effects of HIF-1alpha in the repair of UVB-induced DNA damage.
Rezvani
Hamid Reza
HR
INSERM U876, University Victor Segalen Bordeaux 2, Bordeaux, F-33000 France.
Mahfouf
Walid
W
Ali
Nsrein
N
Chemin
Cecile
C
Ged
Cecile
C
Kim
Arianna L
AL
de Verneuil
Hubert
H
Taïeb
Alain
A
Bickers
David R
DR
Mazurier
Frédéric
F
D001667:Binding, Competitive; D002478:Cells, Cultured; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015536:Down-Regulation; D005786:Gene Expression Regulation; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000378:metabolism*; D015603:Keratinocytes / Q000378:metabolism* / Q000528:radiation effects; D011401:Promoter Regions, Genetic; D020218:Response Elements; D016329:Sp1 Transcription Factor / Q000378:metabolism; D014466:Ultraviolet Rays; D051759:Xeroderma Pigmentosum Group D Protein / Q000378:metabolism*
D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016329:Sp1 Transcription Factor; C086984:XPC protein, human; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human