Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation

  1. Zhengjian Zhang  Is a corresponding author
  2. Zarko Boskovic
  3. Mahmud M Hussain
  4. Wenxin Hu
  5. Carla Inouye
  6. Han-Je Kim
  7. A Katherine Abole
  8. Mary K Doud
  9. Timothy A Lewis
  10. Angela N Koehler
  11. Stuart L Schreiber
  12. Robert Tjian
  1. Janelia Research Campus, Howard Hughes Medical Institute, United States
  2. Howard Hughes Medical Institute, Harvard University, United States
  3. Howard Hughes Medical Institute, University of California, Berkeley, United States
  4. Broad Institute, United States
  5. University of California, Berkeley, United States

Abstract

Intrinsically disordered protein regions (IDRs) are peptide segments that fail to form stable 3-dimensional structures in the absence of partner proteins. They are abundant in eukaryotic proteomes and are often associated with human diseases, but their biological functions have been elusive to study. Here we report the identification of a tin(IV) oxochloride-derived cluster that binds an evolutionarily conserved IDR within the metazoan TFIID transcription complex. Binding arrests an isomerization of promoter-bound TFIID that is required for the engagement of Pol II during the first (de novo) round of transcription initiation. However, the specific chemical probe does not affect reinitiation, which requires the re-entry of Pol II, thus, mechanistically distinguishing these two modes of transcription initiation. This work also suggests a new avenue for targeting the elusive IDRs by harnessing certain features of metal-based complexes for mechanistic studies, and for the development of novel pharmaceutical interventions.

Article and author information

Author details

  1. Zhengjian Zhang

    Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    For correspondence
    zhangzh@janelia.hhmi.org
    Competing interests
    No competing interests declared.
  2. Zarko Boskovic

    Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  3. Mahmud M Hussain

    Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  4. Wenxin Hu

    Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
  5. Carla Inouye

    Li Ka Shing Center for Biomedical and Health Sciences, Department of Molecular and Cell Biology, Howard Hughes Medical Institute, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  6. Han-Je Kim

    Center for the Science of Therapeutics, Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  7. A Katherine Abole

    Department of Chemistry, University of California, Berkeley, Berkeley, United States
    Competing interests
    No competing interests declared.
  8. Mary K Doud

    Center for the Science of Therapeutics, Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  9. Timothy A Lewis

    Center for the Science of Therapeutics, Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  10. Angela N Koehler

    Center for the Science of Therapeutics, Broad Institute, Cambridge, United States
    Competing interests
    No competing interests declared.
  11. Stuart L Schreiber

    Department of Chemistry and Chemical Biology, Howard Hughes Medical Institute, Harvard University, Cambridge, United States
    Competing interests
    No competing interests declared.
  12. Robert Tjian

    Transcription Imaging Consortium, Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    Robert Tjian, President of the Howard Hughes Medical Institute (2009-present), one of the three founding funders of eLife, and a member of eLife's Board of Directors.

Reviewing Editor

  1. Danny Reinberg, Howard Hughes Medical Institute, New York University School of Medicine, United States

Publication history

  1. Received: March 29, 2015
  2. Accepted: August 27, 2015
  3. Accepted Manuscript published: August 28, 2015 (version 1)
  4. Version of Record published: September 25, 2015 (version 2)

Copyright

© 2015, Zhang et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Zhengjian Zhang
  2. Zarko Boskovic
  3. Mahmud M Hussain
  4. Wenxin Hu
  5. Carla Inouye
  6. Han-Je Kim
  7. A Katherine Abole
  8. Mary K Doud
  9. Timothy A Lewis
  10. Angela N Koehler
  11. Stuart L Schreiber
  12. Robert Tjian
(2015)
Chemical perturbation of an intrinsically disordered region of TFIID distinguishes two modes of transcription initiation
eLife 4:e07777.
https://doi.org/10.7554/eLife.07777

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