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

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

Author information

1
Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109, USA.
2
Department of Bioengineering and Therapeutic Sciences, Department of Pharmaceutical Chemistry, California Institute for Quantitative Biomedical Sciences, University of California, San Francisco, San Francisco, CA 94158, USA.
3
Department of Chemistry and Biochemistry, University of Colorado, Boulder, CO 80303, USA.
4
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, PO Box 19024, Mailstop A1-162, Seattle, WA 98109, USA; Génétique des Interactions Macromoléculaires, Institut Pasteur, CNRS UMR3525, 25-28 rue du docteur Roux, 75015 Paris, France.
5
Division of Basic Sciences, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, PO Box 19024, Mailstop A1-162, Seattle, WA 98109, USA.
6
Institute for Systems Biology, 401 Terry Avenue North, Seattle, WA 98109, USA. Electronic address: jranish@systemsbiology.org.

Abstract

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.

PMID:
26340423
PMCID:
PMC4560838
DOI:
10.1016/j.molcel.2015.07.016
[Indexed for MEDLINE]
Free PMC Article

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