Transcription preinitiation complex structure and dynamics provide insight into genetic diseases

doi:https://doi.org/10.1038/s41594-019-0220-3

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:

Yan, Chunli;

; He, Yuan;

; Tsutakawa, Susan E.;

Publication Date:: 2019-05-20

Research Org.:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States). 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.

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                    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.  https://doi.org/10.1038/s41594-019-0220-3

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                    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.  https://doi.org/10.1038/s41594-019-0220-3.

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@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},

  url          = {https://www.osti.gov/biblio/1565757},
  journal      = {Nature Structural & Molecular Biology},

  issn         = {1545-9993},

  number       = 6,

  volume       = 26,

  place        = {United States},

  year         = {2019},

  month        = {5}

}

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

Abstract

Citation Formats

Pre-mRNA Processing Reaches Back toTranscription and Ahead to Translation journal, February 2009

Integrating mRNA Processing with Transcription journal, February 2002

Coupling mRNA processing with transcription in time and space journal, February 2014

The role of general initiation factors in transcription by RNA polymerase II journal, September 1996

TFIIH: New Discoveries Regarding its Mechanisms and Impact on Cancer Treatment journal, January 2016

Transcription Factors as Therapeutic Targets in Chronic Kidney Disease journal, May 2018

Transcriptional regulation and its misregulation in Alzheimer’s disease journal, January 2013

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Contacts in Context: Promoter Specificity and Macromolecular Interactions in Transcription journal, March 1996

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Initiation Complex Structure and Promoter Proofreading journal, July 2011

Structural basis of initial RNA polymerase II transcription: Initial RNA Pol II transcription journal, November 2011

Elongation by RNA polymerase II: the short and long of it journal, October 2004

Near-atomic resolution visualization of human transcription promoter opening journal, May 2016

Structures of transcription pre-initiation complex with TFIIH and Mediator journal, November 2017

Structural visualization of key steps in human transcription initiation journal, February 2013

The cryo-electron microscopy structure of human transcription factor IIH journal, September 2017

Basal Transcription Defect Discriminates between Xeroderma Pigmentosum and Trichothiodystrophy in XPD Patients journal, June 2003

Ten Years of TFIIH journal, January 1998

The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases journal, January 2001

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect journal, February 2016

Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 ( XPD ) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy journal, October 2008

The essential and multifunctional TFIIH complex: Essential and Multi-Functional TFIIH journal, April 2018

Nucleotide Excision Repair and Transcriptional Regulation: TFIIH and Beyond journal, June 2016

TFIIH Subunit Alterations Causing Xeroderma Pigmentosum and Trichothiodystrophy Specifically Disturb Several Steps during Transcription journal, February 2015

TFIIH: when transcription met DNA repair journal, May 2012

Structural insights into transcription initiation by RNA polymerase II journal, December 2013

Architecture of the RNA polymerase II preinitiation complex and mechanism of ATP-dependent promoter opening journal, July 2012

Double-stranded DNA translocase activity of transcription factor TFIIH and the mechanism of RNA polymerase II open complex formation journal, March 2015

Molecular dynamics-based refinement and validation for sub-5 Å cryo-electron microscopy maps journal, July 2016

Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH journal, September 2015

Lack of CAK complex accumulation at DNA damage sites in XP-B and XP-B/CS fibroblasts reveals differential regulation of CAK anchoring to core TFIIH by XPB and XPD helicases during nucleotide excision repair journal, December 2012

Human cyclin-dependent kinase-activating kinase exists in three distinct complexes. journal, June 1996

XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase journal, July 2011

Distinct Roles for the XPB/p52 and XPD/p44 Subcomplexes of TFIIH in Damaged DNA Opening during Nucleotide Excision Repair journal, April 2007

XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations journal, May 2008

XPB: An unconventional SF2 DNA helicase journal, March 2015

Conserved XPB Core Structure and Motifs for DNA Unwinding: Implications for Pathway Selection of Transcription or Excision Repair journal, April 2006

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities journal, February 2013

Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA journal, October 2000

A structure-specific nucleic acid-binding domain conserved among DNA repair proteins journal, May 2014

DNA translocation mechanism of an XPD family helicase journal, December 2018

Structural insight into the TFIIE–TFIIH interaction: TFIIE and p53 share the binding region on TFIIH journal, March 2008

Analysis of the role of TFIIE in basal transcription and TFIIH-mediated carboxy-terminal domain phosphorylation through structure-function studies of TFIIE-alpha. journal, September 1995

NetworkView: 3D display and analysis of protein{middle dot}RNA interaction networks journal, September 2012

DNA topology and a minimal set of basal factors for transcription by RNA polymerase II journal, May 1993

Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients journal, November 2009

Shining a Light on Xeroderma Pigmentosum journal, March 2012

GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy journal, April 2016

The complete structure of the human TFIIH core complex journal, March 2019

GeneSilico protein structure prediction meta-server journal, July 2003

Coot model-building tools for molecular graphics journal, November 2004

Comparative Protein Modelling by Satisfaction of Spatial Restraints journal, December 1993

The intricate network between the p34 and p44 subunits is central to the activity of the transcription/DNA repair factor TFIIH journal, August 2017

Solution Structure of the N-terminal Domain of the Human TFIIH MAT1 Subunit: NEW INSIGHTS INTO THE RING FINGER FAMILY journal, October 2000

UCSF Chimera?A visualization system for exploratory research and analysis journal, January 2004

Flexible Fitting of Atomic Structures into Electron Microscopy Maps Using Molecular Dynamics journal, May 2008

PHENIX: a comprehensive Python-based system for macromolecular structure solution journal, January 2010

Real-space refinement in PHENIX for cryo-EM and crystallography journal, May 2018

The Amber biomolecular simulation programs journal, January 2005

Comparison of simple potential functions for simulating liquid water journal, July 1983

Reversible multiple time scale molecular dynamics journal, August 1992

NAMD2: Greater Scalability for Parallel Molecular Dynamics journal, May 1999

Scalable molecular dynamics with NAMD journal, January 2005

ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB journal, July 2015

CURVES+ web server for analyzing and visualizing the helical, backbone and groove parameters of nucleic acid structures journal, May 2011

Essential dynamics of proteins journal, December 1993

PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data journal, June 2013

VMD: Visual molecular dynamics journal, February 1996

Software news and updates carma: A molecular dynamics analysis program journal, January 2006

Pre-mRNA Processing Reaches Back toTranscription and Ahead to Translation
journal, February 2009

Integrating mRNA Processing with Transcription
journal, February 2002

Coupling mRNA processing with transcription in time and space
journal, February 2014

The role of general initiation factors in transcription by RNA polymerase II
journal, September 1996

TFIIH: New Discoveries Regarding its Mechanisms and Impact on Cancer Treatment
journal, January 2016

Transcription Factors as Therapeutic Targets in Chronic Kidney Disease
journal, May 2018

Transcriptional regulation and its misregulation in Alzheimer’s disease
journal, January 2013

Transcriptional Regulation and Its Misregulation in Disease
journal, March 2013

Contacts in Context: Promoter Specificity and Macromolecular Interactions in Transcription
journal, March 1996

Structural basis of eukaryotic gene transcription
journal, November 2004

Five intermediate complexes in transcription initiation by RNA polymerase II
journal, February 1989

Initiation Complex Structure and Promoter Proofreading
journal, July 2011

Structural basis of initial RNA polymerase II transcription: Initial RNA Pol II transcription
journal, November 2011

Elongation by RNA polymerase II: the short and long of it
journal, October 2004

Near-atomic resolution visualization of human transcription promoter opening
journal, May 2016

Structures of transcription pre-initiation complex with TFIIH and Mediator
journal, November 2017

Structural visualization of key steps in human transcription initiation
journal, February 2013

The cryo-electron microscopy structure of human transcription factor IIH
journal, September 2017

Basal Transcription Defect Discriminates between Xeroderma Pigmentosum and Trichothiodystrophy in XPD Patients
journal, June 2003

Ten Years of TFIIH
journal, January 1998

The xeroderma pigmentosum group D (XPD) gene: one gene, two functions, three diseases
journal, January 2001

Deep phenotyping of 89 xeroderma pigmentosum patients reveals unexpected heterogeneity dependent on the precise molecular defect
journal, February 2016

Persistence of repair proteins at unrepaired DNA damage distinguishes diseases with ERCC2 ( XPD ) mutations: cancer-prone xeroderma pigmentosum vs. non-cancer-prone trichothiodystrophy
journal, October 2008

The essential and multifunctional TFIIH complex: Essential and Multi-Functional TFIIH
journal, April 2018

Nucleotide Excision Repair and Transcriptional Regulation: TFIIH and Beyond
journal, June 2016

TFIIH Subunit Alterations Causing Xeroderma Pigmentosum and Trichothiodystrophy Specifically Disturb Several Steps during Transcription
journal, February 2015

TFIIH: when transcription met DNA repair
journal, May 2012

Structural insights into transcription initiation by RNA polymerase II
journal, December 2013

Architecture of the RNA polymerase II preinitiation complex and mechanism of ATP-dependent promoter opening
journal, July 2012

Double-stranded DNA translocase activity of transcription factor TFIIH and the mechanism of RNA polymerase II open complex formation
journal, March 2015

Molecular dynamics-based refinement and validation for sub-5 Å cryo-electron microscopy maps
journal, July 2016

Architecture of the Human and Yeast General Transcription and DNA Repair Factor TFIIH
journal, September 2015

Lack of CAK complex accumulation at DNA damage sites in XP-B and XP-B/CS fibroblasts reveals differential regulation of CAK anchoring to core TFIIH by XPB and XPD helicases during nucleotide excision repair
journal, December 2012

Human cyclin-dependent kinase-activating kinase exists in three distinct complexes.
journal, June 1996

XPB and XPD helicases in TFIIH orchestrate DNA duplex opening and damage verification to coordinate repair with transcription and cell cycle via CAK kinase
journal, July 2011

Distinct Roles for the XPB/p52 and XPD/p44 Subcomplexes of TFIIH in Damaged DNA Opening during Nucleotide Excision Repair
journal, April 2007

XPD Helicase Structures and Activities: Insights into the Cancer and Aging Phenotypes from XPD Mutations
journal, May 2008

XPB: An unconventional SF2 DNA helicase
journal, March 2015

Conserved XPB Core Structure and Motifs for DNA Unwinding: Implications for Pathway Selection of Transcription or Excision Repair
journal, April 2006

ARCH domain of XPD, an anchoring platform for CAK that conditions TFIIH DNA repair and transcription activities
journal, February 2013

Crystal structures of mismatch repair protein MutS and its complex with a substrate DNA
journal, October 2000

A structure-specific nucleic acid-binding domain conserved among DNA repair proteins
journal, May 2014

DNA translocation mechanism of an XPD family helicase
journal, December 2018

Structural insight into the TFIIE–TFIIH interaction: TFIIE and p53 share the binding region on TFIIH
journal, March 2008

Analysis of the role of TFIIE in basal transcription and TFIIH-mediated carboxy-terminal domain phosphorylation through structure-function studies of TFIIE-alpha.
journal, September 1995

NetworkView: 3D display and analysis of protein{middle dot}RNA interaction networks
journal, September 2012

DNA topology and a minimal set of basal factors for transcription by RNA polymerase II
journal, May 1993

Both XPD alleles contribute to the phenotype of compound heterozygote xeroderma pigmentosum patients
journal, November 2009

Shining a Light on Xeroderma Pigmentosum
journal, March 2012

GTF2E2 Mutations Destabilize the General Transcription Factor Complex TFIIE in Individuals with DNA Repair-Proficient Trichothiodystrophy
journal, April 2016

The complete structure of the human TFIIH core complex
journal, March 2019

GeneSilico protein structure prediction meta-server
journal, July 2003

Coot model-building tools for molecular graphics
journal, November 2004

Comparative Protein Modelling by Satisfaction of Spatial Restraints
journal, December 1993

The intricate network between the p34 and p44 subunits is central to the activity of the transcription/DNA repair factor TFIIH
journal, August 2017

Solution Structure of the N-terminal Domain of the Human TFIIH MAT1 Subunit: NEW INSIGHTS INTO THE RING FINGER FAMILY
journal, October 2000

UCSF Chimera?A visualization system for exploratory research and analysis
journal, January 2004

Flexible Fitting of Atomic Structures into Electron Microscopy Maps Using Molecular Dynamics
journal, May 2008

PHENIX: a comprehensive Python-based system for macromolecular structure solution
journal, January 2010

Real-space refinement in PHENIX for cryo-EM and crystallography
journal, May 2018

The Amber biomolecular simulation programs
journal, January 2005

Comparison of simple potential functions for simulating liquid water
journal, July 1983

Reversible multiple time scale molecular dynamics
journal, August 1992

NAMD2: Greater Scalability for Parallel Molecular Dynamics
journal, May 1999

Scalable molecular dynamics with NAMD
journal, January 2005

ff14SB: Improving the Accuracy of Protein Side Chain and Backbone Parameters from ff99SB
journal, July 2015

CURVES+ web server for analyzing and visualizing the helical, backbone and groove parameters of nucleic acid structures
journal, May 2011

Essential dynamics of proteins
journal, December 1993

PTRAJ and CPPTRAJ: Software for Processing and Analysis of Molecular Dynamics Trajectory Data
journal, June 2013

VMD: Visual molecular dynamics
journal, February 1996

Software news and updates carma: A molecular dynamics analysis program
journal, January 2006