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Title: Transcription preinitiation complex structure and dynamics provide insight into genetic diseases

Abstract

Transcription preinitiation complexes (PICs) are vital assemblies whose function underlies the expression of protein-encoding genes. Cryo-EM advances have begun to uncover their structural organization. Nevertheless, functional analyses are hindered by incompletely modeled regions. Here we integrate all available cryo-EM data to build a practically complete human PIC structural model. This enables simulations that reveal the assembly’s global motions, define PIC partitioning into dynamic communities and delineate how structural modules function together to remodel DNA. We identify key TFIIE–p62 interactions that link core-PIC to TFIIH. p62 rigging interlaces p34, p44 and XPD while capping the DNA-binding and ATP-binding sites of XPD. PIC kinks and locks substrate DNA, creating negative supercoiling within the Pol II cleft to facilitate promoter opening. Mapping disease mutations associated with xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome onto defined communities reveals clustering into three mechanistic classes that affect TFIIH helicase functions, protein interactions and interface dynamics.

Authors:
; ORCiD logo; ; ORCiD logo; ; ORCiD logo
Publication Date:
Research Org.:
Oak Ridge National Laboratory, Oak Ridge Leadership Computing Facility (OLCF), Oak Ridge, TN (United States); UT- Battelle LLC/ORNL, Oak Ridge, TN (United States)
Sponsoring Org.:
USDOE Office of Science (SC)
OSTI Identifier:
1565757
DOE Contract Number:  
AC05-00OR22725
Resource Type:
Journal Article
Journal Name:
Nature Structural & Molecular Biology
Additional Journal Information:
Journal Volume: 26; Journal Issue: 6; Journal ID: ISSN 1545-9993
Publisher:
Nature Publishing Group
Country of Publication:
United States
Language:
English
Subject:
Biochemistry & Molecular Biology; Biophysics; Cell Biology

Citation Formats

Yan, Chunli, Dodd, Thomas, He, Yuan, Tainer, John A., Tsutakawa, Susan E., and Ivanov, Ivaylo. Transcription preinitiation complex structure and dynamics provide insight into genetic diseases. United States: N. p., 2019. Web. doi:10.1038/s41594-019-0220-3.
Yan, Chunli, Dodd, Thomas, He, Yuan, Tainer, John A., Tsutakawa, Susan E., & Ivanov, Ivaylo. Transcription preinitiation complex structure and dynamics provide insight into genetic diseases. United States. doi:10.1038/s41594-019-0220-3.
Yan, Chunli, Dodd, Thomas, He, Yuan, Tainer, John A., Tsutakawa, Susan E., and Ivanov, Ivaylo. Mon . "Transcription preinitiation complex structure and dynamics provide insight into genetic diseases". United States. doi:10.1038/s41594-019-0220-3.
@article{osti_1565757,
title = {Transcription preinitiation complex structure and dynamics provide insight into genetic diseases},
author = {Yan, Chunli and Dodd, Thomas and He, Yuan and Tainer, John A. and Tsutakawa, Susan E. and Ivanov, Ivaylo},
abstractNote = {Transcription preinitiation complexes (PICs) are vital assemblies whose function underlies the expression of protein-encoding genes. Cryo-EM advances have begun to uncover their structural organization. Nevertheless, functional analyses are hindered by incompletely modeled regions. Here we integrate all available cryo-EM data to build a practically complete human PIC structural model. This enables simulations that reveal the assembly’s global motions, define PIC partitioning into dynamic communities and delineate how structural modules function together to remodel DNA. We identify key TFIIE–p62 interactions that link core-PIC to TFIIH. p62 rigging interlaces p34, p44 and XPD while capping the DNA-binding and ATP-binding sites of XPD. PIC kinks and locks substrate DNA, creating negative supercoiling within the Pol II cleft to facilitate promoter opening. Mapping disease mutations associated with xeroderma pigmentosum, trichothiodystrophy and Cockayne syndrome onto defined communities reveals clustering into three mechanistic classes that affect TFIIH helicase functions, protein interactions and interface dynamics.},
doi = {10.1038/s41594-019-0220-3},
journal = {Nature Structural & Molecular Biology},
issn = {1545-9993},
number = 6,
volume = 26,
place = {United States},
year = {2019},
month = {5}
}

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