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Title: The cryo-electron microscopy structure of human transcription factor IIH

Abstract

We report human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 Å resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Also, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.

Authors:
 [1];  [2];  [3];  [4];  [5];  [6]
  1. Univ. of California, Berkeley, CA (United States). California Institute for Quantitative Biology (QB3); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bio-Imaging Division
  2. Univ. of California, Berkeley, CA (United States). California Institute for Quantitative Biology (QB3) and Miller Institute for Basic Research in Science; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bio-Imaging Division
  3. Univ. of California, Berkeley, CA (United States). Howard Hughes Medical Institute
  4. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bio-Imaging Division
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bio-Imaging Division; Univ. of California, Berkeley, CA (United States). Department of Bioengineering
  6. Univ. of California, Berkeley, CA (United States). California Institute for Quantitative Biology (QB3), Howard Hughes Medical Institute and Department of Molecular and Cell Biology; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Molecular Biophysics and Integrative Bio-Imaging Division
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Lawrence Berkeley National Laboratory-National Energy Research Scientific Computing Center
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1437969
Grant/Contract Number:  
AC02-05CH11231
Resource Type:
Accepted Manuscript
Journal Name:
Nature (London)
Additional Journal Information:
Journal Name: Nature (London); Journal Volume: 549; Journal Issue: 7672; Related Information: © 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.; Journal ID: ISSN 0028-0836
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES; 37 INORGANIC, ORGANIC, PHYSICAL, AND ANALYTICAL CHEMISTRY; Cryoelectron microscopy; Supramolecular assembly; Transcription

Citation Formats

Greber, Basil J., Nguyen, Thi Hoang Duong, Fang, Jie, Afonine, Pavel V., Adams, Paul D., and Nogales, Eva. The cryo-electron microscopy structure of human transcription factor IIH. United States: N. p., 2017. Web. doi:10.1038/nature23903.
Greber, Basil J., Nguyen, Thi Hoang Duong, Fang, Jie, Afonine, Pavel V., Adams, Paul D., & Nogales, Eva. The cryo-electron microscopy structure of human transcription factor IIH. United States. doi:10.1038/nature23903.
Greber, Basil J., Nguyen, Thi Hoang Duong, Fang, Jie, Afonine, Pavel V., Adams, Paul D., and Nogales, Eva. Wed . "The cryo-electron microscopy structure of human transcription factor IIH". United States. doi:10.1038/nature23903. https://www.osti.gov/servlets/purl/1437969.
@article{osti_1437969,
title = {The cryo-electron microscopy structure of human transcription factor IIH},
author = {Greber, Basil J. and Nguyen, Thi Hoang Duong and Fang, Jie and Afonine, Pavel V. and Adams, Paul D. and Nogales, Eva},
abstractNote = {We report human transcription factor IIH (TFIIH) is part of the general transcriptional machinery required by RNA polymerase II for the initiation of eukaryotic gene transcription. Composed of ten subunits that add up to a molecular mass of about 500 kDa, TFIIH is also essential for nucleotide excision repair. The seven-subunit TFIIH core complex formed by XPB, XPD, p62, p52, p44, p34, and p8 is competent for DNA repair, while the CDK-activating kinase subcomplex, which includes the kinase activity of CDK7 as well as the cyclin H and MAT1 subunits, is additionally required for transcription initiation. Mutations in the TFIIH subunits XPB, XPD, and p8 lead to severe premature ageing and cancer propensity in the genetic diseases xeroderma pigmentosum, Cockayne syndrome, and trichothiodystrophy, highlighting the importance of TFIIH for cellular physiology. Here we present the cryo-electron microscopy structure of human TFIIH at 4.4 Å resolution. The structure reveals the molecular architecture of the TFIIH core complex, the detailed structures of its constituent XPB and XPD ATPases, and how the core and kinase subcomplexes of TFIIH are connected. Also, our structure provides insight into the conformational dynamics of TFIIH and the regulation of its activity.},
doi = {10.1038/nature23903},
journal = {Nature (London)},
number = 7672,
volume = 549,
place = {United States},
year = {2017},
month = {9}
}

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Cited by: 12 works
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Figures / Tables:

Figure 1. Figure 1.: Cryo-EM reconstruction of human TFIIH a, Cryo-EM map of TFIIH, colour coded and labelled according to constituent subunits; unassigned density is grey. b, Front and back views of the molecular structure of TFIIH. Protein subunits are labelled. Unassigned secondary structure elements attributed to XPB and p52 are lightmore » blue and pale yellow, respectively; remaining unassigned elements, grey. c, Unassigned secondary structure elements and remaining unassigned density in the p34–p44 hinge region (teal) may correspond to p62 and the zinc-binding domains of p34 and p44. Positions of crosslinks between p62 and other TFIIH core proteins7 shown by spheres coloured according to the crosslinked partner; crosslinks from studies of yeast TFIIH indicated by ‘Y’.« less

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