XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha.

Anne Keriel (1) , Anne Stary (2) , Alain Sarasin (2) , Cécile Egly , Jean Marc Egly (3)

1 INSERM - Institut National de la Santé et de la Recherche Médicale
2 ERIGC - Etude des relations instabilité génétique et cancer
3 IGBMC - Institut de génétique et biologie moléculaire et cellulaire

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.

Domaines: Bactériologie; Virologie; Maladies infectieuses

Anne Keriel, Anne Stary, Alain Sarasin, Cécile Egly, Jean Marc Egly. XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha.. Cell, 2002, 109 (1), pp.125-35. ⟨hal-01994375⟩