Dysregulation of the Peroxisome Proliferator-Activated Receptor Target Genes by XPD Mutations

Abstract

Mutations in the XPD subunit of TFIIH give rise to human genetic disorders initially defined as DNA repair syndromes. Nevertheless, xeroderma pigmentosum (XP) group D (XP-D) patients develop clinical features such as hypoplasia of the adipose tissue, implying a putative transcriptional defect. Knowing that peroxisome proliferator-activated receptors (PPARs) are implicated in lipid metabolism, we investigated the expression of PPAR target genes in the adipose tissues and the livers of XPD-deficient mice and found that (i) some genes are abnormally overexpressed in a ligand-independent manner which parallels an increase in the recruitment of RNA polymerase (pol) II but not PPARs on their promoter and (ii) upon treatment with PPAR ligands, other genes are much less induced compared to the wild type, which is due to a lower recruitment of both PPARs and RNA pol II. The defect in transactivation by PPARs is likely attributable to their weaker phosphorylation by the cdk7 kinase of TFIIH. Having identified the phosphorylated residues in PPAR isotypes, we demonstrate how their transactivation defect in XPD-deficient cells can be circumvented by overexpression of either a wild-type XPD or a constitutively phosphorylated PPAR S/E. This work emphasizes that underphosphorylation of PPARs affects their transactivation and consequently the expression of PPAR target genes, thus contributing in part to the XP-D phenotype.

ACKNOWLEDGMENTS

We thank P. Brousset (CHU Purpan, INSERM U563, Toulouse, France), M. Doffoel (Clinique Med B, Hospices Civils de Strasbourg, Strasbourg, France), and M. P. Chenard (Service d'anatomo-pathologie, Hôpital Hautepierre, Strasbourg, France) for fruitful discussions and P. Laine for critical reading of the manuscript. We are grateful to I. Kolb-Cheynel and J. L. Weickert for the design and production of recombinant baculoviruses; M. Argentini for mass spectral analysis; M. C. Antal, M. Duval, and M. Selloum for expertise in phenotyping mice; and J. Auwerx, P. Grimaldi, and M. Dauca for the pPPAR-RE-Luc, PSG5-rat PPARα, pSG5-human PPARγ1 and -2, and pcDNA-mouse PPARδ constructs.

These studies were supported by CNRS, INSERM, and grants from the Association pour la Recherche sur le Cancer, the European Community (QLG1-1999 and QLRT-1999-02002), the Research Ministry ACI Biologie Cellulaire et Structurale (3-2-535), the Institut des Maladies Rares (A03098MS), and the Commissariat à l'Energie Atomique. E.C. is a recipient of a grant from the Association pour la Recherche contre le Cancer. P.D. is the recipient of a fellowship from the Fondation Lefoulon-Delalande, and the 2000 Descartes Prize was awarded to J.-M.E. by the European Economic Community. C.L. is a recipient of a Fondation pour la Recherche Médicale fellowship.