Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH

Mol Cell. 2015 Sep 3;59(5):794-806. doi: 10.1016/j.molcel.2015.07.016.


TFIIH is essential for both RNA polymerase II transcription and DNA repair, and mutations in TFIIH can result in human disease. Here, we determine the molecular architecture of human and yeast TFIIH by an integrative approach using chemical crosslinking/mass spectrometry (CXMS) data, biochemical analyses, and previously published electron microscopy maps. We identified four new conserved "topological regions" that function as hubs for TFIIH assembly and more than 35 conserved topological features within TFIIH, illuminating a network of interactions involved in TFIIH assembly and regulation of its activities. We show that one of these conserved regions, the p62/Tfb1 Anchor region, directly interacts with the DNA helicase subunit XPD/Rad3 in native TFIIH and is required for the integrity and function of TFIIH. We also reveal the structural basis for defects in patients with xeroderma pigmentosum and trichothiodystrophy, with mutations found at the interface between the p62 Anchor region and the XPD subunit.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cross-Linking Reagents
  • DNA Helicases / chemistry
  • DNA Helicases / genetics
  • DNA Helicases / metabolism
  • DNA Repair
  • Humans
  • Mass Spectrometry
  • Models, Molecular
  • Mutation
  • Protein Interaction Domains and Motifs
  • Protein Subunits
  • Saccharomyces cerevisiae / genetics
  • Saccharomyces cerevisiae / metabolism
  • Saccharomyces cerevisiae Proteins / chemistry*
  • Saccharomyces cerevisiae Proteins / genetics
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Transcription Factor TFIIH / chemistry*
  • Transcription Factor TFIIH / genetics
  • Transcription Factor TFIIH / metabolism*
  • Transcription Factors, TFII / chemistry
  • Transcription Factors, TFII / genetics
  • Transcription Factors, TFII / metabolism
  • Transcription, Genetic
  • Xeroderma Pigmentosum / genetics
  • Xeroderma Pigmentosum / metabolism
  • Xeroderma Pigmentosum Group D Protein / chemistry
  • Xeroderma Pigmentosum Group D Protein / genetics
  • Xeroderma Pigmentosum Group D Protein / metabolism


  • Cross-Linking Reagents
  • Protein Subunits
  • Saccharomyces cerevisiae Proteins
  • TFB1 protein, S cerevisiae
  • Transcription Factors, TFII
  • Transcription Factor TFIIH
  • Rad3 protein, S cerevisiae
  • DNA Helicases
  • Xeroderma Pigmentosum Group D Protein
  • ERCC2 protein, human