Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription

  1. Rui Gao
  2. Anirban Chakraborty
  3. Charlene Geater
  4. Subrata Pradhan
  5. Kara L Gordon
  6. Jeffrey Snowden
  7. Subo Yuan
  8. Audrey S Dickey
  9. Sanjeev Choudhary
  10. Tetsuo Ashizawa
  11. Lisa M Ellerby
  12. Albert R La Spada
  13. Leslie M Thompson
  14. Tapas K Hazra
  15. Partha S Sarkar  Is a corresponding author
  1. University of Texas Medical Branch, United States
  2. University of California, Irvine, United States
  3. Duke University School of Medicine, United States
  4. Sam Houston State University, United States
  5. Houston Methodist Research Institute, United States
  6. Buck Institute for Research on Aging, United States

Abstract

How huntingtin (HTT) triggers neurotoxicity in Huntington's disease (HD) remains unclear. We report that HTT forms a transcription-coupled DNA repair (TCR) complex with RNA polymerase II subunit A (POLR2A), ataxin-3, the DNA repair enzyme polynucleotide-kinase-3'-phosphatase (PNKP), and cyclic AMP-response element-binding (CREB) protein (CBP). This complex senses and facilitates DNA damage repair during transcriptional elongation, but its functional integrity is impaired by mutant HTT. Abrogated PNKP activity results in persistent DNA break accumulation, preferentially in actively transcribed genes, and aberrant activation of DNA damage-response ataxia telangiectasia-mutated (ATM) signaling in HD transgenic mouse and cell models. A concomitant decrease in Ataxin-3 activity facilitates CBP ubiquitination and degradation, adversely impacting transcription and DNA repair. Increasing PNKP activity in mutant cells improves genome integrity and cell survival. These findings suggest a potential molecular mechanism of how mutant HTT activates DNA damage-response pro-degenerative pathways and impairs transcription, triggering neurotoxicity and functional decline in HD.

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All data generated are included in the manuscript and supporting files.

Article and author information

Author details

  1. Rui Gao

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. Anirban Chakraborty

    Department of Internal Medicine, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
  3. Charlene Geater

    Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Subrata Pradhan

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Kara L Gordon

    Department of Neurology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Jeffrey Snowden

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Subo Yuan

    Department of Neuroscience, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Audrey S Dickey

    Department of Neurology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
  9. Sanjeev Choudhary

    Department of Biochemistry, Cell Biology and Genetics, Sam Houston State University, Huntsville, United States
    Competing interests
    The authors declare that no competing interests exist.
  10. Tetsuo Ashizawa

    Department of Neurology, Houston Methodist Research Institute, Houston, United States
    Competing interests
    The authors declare that no competing interests exist.
  11. Lisa M Ellerby

    Buck Institute for Research on Aging, Novato, United States
    Competing interests
    The authors declare that no competing interests exist.
  12. Albert R La Spada

    Department of Neurology, Duke University School of Medicine, Durham, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6151-2964
  13. Leslie M Thompson

    Department of Psychiatry and Human Behavior, University of California, Irvine, Irvine, United States
    Competing interests
    The authors declare that no competing interests exist.
  14. Tapas K Hazra

    Department of Internal Medicine, University of Texas Medical Branch, Galveston, United States
    Competing interests
    The authors declare that no competing interests exist.
  15. Partha S Sarkar

    Department of Neurology, University of Texas Medical Branch, Galveston, United States
    For correspondence
    pssarkar@utmb.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2885-8100

Funding

NIH Office of the Director (NSO79541-01)

  • Tapas K Hazra
  • Partha S Sarkar

NIH Office of the Director (NS073976)

  • Tapas K Hazra

Hereditary Disease Foundation (Postdoctoral Fellowship)

  • Charlene Geater

Mitchel Center for Neurodegenerative Diseases, University of Texas Medical Branch, Galveston, TX (Developmental Grant)

  • Partha S Sarkar

NIH Office of the Director (EY026089-01A1)

  • Partha S Sarkar

NIH Office of the Director (NS100529)

  • Lisa M Ellerby

NIH Office of the Director (AG033082)

  • Albert R La Spada

NIH Office of the Director (NS065874)

  • Albert R La Spada

NIH Office of the Director (NS089076)

  • Leslie M Thompson

NIH Office of the Director (NS090390)

  • Leslie M Thompson

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Reviewing Editor

  1. Harry T Orr, University of Minnesota, United States

Ethics

Animal experimentation: All procedures involving animals were in accordance with the National Institutes of Health Guide for the care and use of Laboratory Animals, and approved by the Institutional Animal Care and Use Committee of University of California Irivine (protocol #: AUP-18-155); and Duke University (protocol #: A225-17-09).

Version history

  1. Received: October 19, 2018
  2. Accepted: April 16, 2019
  3. Accepted Manuscript published: April 17, 2019 (version 1)
  4. Version of Record published: May 21, 2019 (version 2)

Copyright

© 2019, Gao 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. Rui Gao
  2. Anirban Chakraborty
  3. Charlene Geater
  4. Subrata Pradhan
  5. Kara L Gordon
  6. Jeffrey Snowden
  7. Subo Yuan
  8. Audrey S Dickey
  9. Sanjeev Choudhary
  10. Tetsuo Ashizawa
  11. Lisa M Ellerby
  12. Albert R La Spada
  13. Leslie M Thompson
  14. Tapas K Hazra
  15. Partha S Sarkar
(2019)
Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
eLife 8:e42988.
https://doi.org/10.7554/eLife.42988

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https://doi.org/10.7554/eLife.42988