Transcription preinitiation complex structure and dynamics provide insight into genetic diseases

Chunli Yan; Thomas Dodd; Yuan He; John A. Tainer; Susan E. Tsutakawa; Ivaylo Ivanov

doi:10.1038/s41594-019-0220-3

Transcription preinitiation complex structure and dynamics provide insight into genetic diseases

Chunli Yan, Thomas Dodd, Yuan He, John A. Tainer, Susan E. Tsutakawa, Ivaylo Ivanov^*

^*Corresponding author for this work

Molecular Biosciences

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

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.

Original language	English (US)
Pages (from-to)	397-406
Number of pages	10
Journal	Nature Structural and Molecular Biology
Volume	26
Issue number	6
DOIs	https://doi.org/10.1038/s41594-019-0220-3
State	Published - Jun 1 2019

Funding

We thank S. Schilbach and P. Cramer for sharing the EMD-3846 cryo-EM density map and model before these became available from EMDB. We thank E. Nogales for insightful discussions. This work was supported by National Institutes of Health (NIH) grant No. GM110387 to I.I. Work on TFIIH by Y.H., S.E.T. and J.A.T. is supported by NIH grant No. P01 CA092584. J.A.T. is also supported for structural analyses by NIH grant No. R35 CA220430, a Robert A. Welch Chemistry Chair and the Cancer Prevention and Research Institute of Texas (Nos. RR140052 and RP180813). Computational resources were provided in part by an allocation from the National Science Foundation XSEDE program (No. CHE110042) to I.I. An award of computer time to I.I. was provided by the INCITE program. This research also used resources of the Oak Ridge Leadership Computing Facility, which is a DOE Office of Science User Facility supported under Contract No. DE-AC05-00OR22725.

ASJC Scopus subject areas

Structural Biology
Molecular Biology

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10.1038/s41594-019-0220-3

Cite this

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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{\textquoteright}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.",

author = "Chunli Yan and Thomas Dodd and Yuan He and Tainer, {John A.} and Tsutakawa, {Susan E.} and Ivaylo Ivanov",

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AU - Dodd, Thomas

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AU - Ivanov, Ivaylo

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N2 - 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.

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Transcription preinitiation complex structure and dynamics provide insight into genetic diseases

Abstract

Funding

ASJC Scopus subject areas

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Human holo-PIC in the closed state

Structure of the human apo TFIIH

Cite this

Transcription preinitiation complex structure and dynamics provide insight into genetic diseases

Abstract

Funding

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Datasets

Human holo-PIC in the closed state

Structure of the human apo TFIIH

Cite this