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Updated: May 5, 2026

A High Resolution Method to Monitor Phosphorylation-dependent Activation of IRF3
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XPD mutations prevent TFIIH-dependent transactivation by nuclear receptors and phosphorylation of RARalpha

Anne Keriel1, Anne Stary, Alain Sarasin

  • 1Institut de Génétique et de Biologie Moléculaire et Cellulaire, CNRS/INSERM/ULP, BP 163, 67404 Illkirch Cedex, C. U., Strasbourg, France.

Cell
|April 17, 2002
PubMed

Insights

Mutations in the XPD gene, linked to Xeroderma pigmentosum (XP), impair nuclear receptor function beyond DNA repair. This study reveals XPD

Area of Science:

  • Molecular Biology
  • Genetics
  • Biochemistry

Background:

  • Xeroderma pigmentosum (XP) is a rare genetic disorder caused by mutations in the XPD gene, a component of the transcription/repair factor TFIIH.
  • XP phenotypes suggest roles for XPD beyond DNA repair, but these are not fully understood.

Purpose of the Study:

  • To investigate the non-DNA repair functions of the XPD gene.
  • To explore the impact of XPD mutations on nuclear receptor-mediated transactivation.

Main Methods:

  • Analysis of nuclear receptor transactivation in cells from XP-D patients.
  • Investigating the role of XPD in the phosphorylation of the RARalpha nuclear receptor.
  • Utilizing overexpression of wild-type XPD and a mutated RARalpha (RARalphaS77E) to assess functional restoration.

Main Results:

  • XPD mutations reduce ligand-dependent transactivation of nuclear receptors like RARalpha, ERalpha, and AR.
  • The XPD mutation impairs the cdk7 kinase activity within TFIIH, affecting RARalpha phosphorylation.
  • Restoration of transactivation was observed with wild-type XPD or RARalphaS77E, indicating the importance of proper RARalpha phosphorylation.

Conclusions:

  • The XPD subunit of TFIIH plays a crucial role in regulating nuclear receptor activity through phosphorylation.
  • This phosphorylation, mediated by the cdk7 kinase, is essential for ligand-dependent gene activation.
  • XPD's function extends beyond DNA repair, impacting hormonal gene regulation and potentially contributing to XP phenotypes.

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