Dysregulation of the peroxisome proliferator-activated receptor target genes by XPD mutations

Area of Science:

• Molecular Biology
• Genetics
• Biochemistry

Background:

• Mutations in the XPD subunit of TFIIH cause DNA repair disorders like xeroderma pigmentosum (XP) group D (XP-D).
• XP-D patients exhibit adipose tissue hypoplasia, suggesting a transcriptional defect beyond DNA repair.
• Peroxisome proliferator-activated receptors (PPARs) are key regulators of lipid metabolism.

Purpose of the Study:

• To investigate the role of XPD mutations in PPAR-mediated gene expression in lipid metabolism.
• To elucidate the mechanism linking XPD deficiency to transcriptional dysregulation of PPAR target genes.

Main Methods:

• Analysis of PPAR target gene expression in adipose tissue and liver of XPD-deficient mice.
• Assessment of RNA polymerase II and PPAR recruitment to target gene promoters.
• Investigation of PPAR phosphorylation by cdk7 kinase and its impact on transactivation.

Main Results:

• XPD-deficient cells show ligand-independent overexpression of some PPAR target genes and reduced induction of others upon PPAR ligand treatment.
• This dysregulation is linked to altered recruitment of RNA polymerase II and PPARs to promoters.
• PPAR transactivation defects in XPD-deficient cells are associated with reduced PPAR phosphorylation by cdk7, a kinase component of TFIIH.

Conclusions:

• Underphosphorylation of PPARs due to XPD deficiency impairs their transactivation function.
• This defect in PPAR-mediated transcription contributes to the XP-D phenotype, particularly affecting lipid metabolism.
• Restoring XPD function or using constitutively phosphorylated PPAR variants can overcome the transactivation defect.