XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha.
Inherited mutations in the XPD subunit of the general transcription/repair factor TFIIH yield the rare genetic disorder Xeroderma pigmentosum (XP), the phenotypes of which cannot be explained solely on the basis of a DNA repair defect. In cells derived from XP-D patients, we observed a reduction of the ligand-dependent transactivation mediated by several nuclear receptors (RARalpha, ERalpha, and AR). We demonstrate that the XPD mutation alters cdk7 function in RARalpha phosphorylation. Transactivation is restored upon overexpression of either the wild-type XPD or the RARalphaS77E (a mutation which mimics phosphorylated RARalpha). Thus, we demonstrate that the cdk7 kinase of TFIIH phosphorylates the nuclear receptor, then allowing ligand-dependent control of the activation of the hormone-responsive genes.
Keriel
Anne
A
Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C. U., Strasbourg, France.
Stary
Anne
A
Sarasin
Alain
A
Rochette-Egly
Cécile
C
Egly
Jean Marc
JM
D000818:Animals; D002467:Cell Nucleus / Q000235:genetics / Q000378:metabolism; D018844:Cyclin-Dependent Kinases; D004265:DNA Helicases; D004268:DNA-Binding Proteins; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism; D005786:Gene Expression Regulation / Q000502:physiology; D006367:HeLa Cells / Q000166:cytology / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D011506:Proteins / Q000235:genetics* / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics* / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics* / Q000378:metabolism; D000072482:Retinoic Acid Receptor alpha; D015398:Signal Transduction / Q000235:genetics; D051758:Transcription Factor TFIIH; D014157:Transcription Factors / Q000235:genetics* / Q000378:metabolism; D019473:Transcription Factors, TFII; D014158:Transcription, Genetic / Q000235:genetics*; D015533:Transcriptional Activation / Q000235:genetics*; D014983:Xeroderma Pigmentosum / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D051759:Xeroderma Pigmentosum Group D Protein; D000095043:Cyclin-Dependent Kinase-Activating Kinase
D004268:DNA-Binding Proteins; D011506:Proteins; C000607071:RARA protein, human; D018160:Receptors, Cytoplasmic and Nuclear; D018168:Receptors, Retinoic Acid; D000072482:Retinoic Acid Receptor alpha; D014157:Transcription Factors; D019473:Transcription Factors, TFII; D051758:Transcription Factor TFIIH; D017346:Protein Serine-Threonine Kinases; D018844:Cyclin-Dependent Kinases; D004265:DNA Helicases; D051759:Xeroderma Pigmentosum Group D Protein; C497292:ERCC2 protein, human; D000095043:Cyclin-Dependent Kinase-Activating Kinase; C000722416:CDK7 protein, human