Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
- University of Texas Medical Branch, United States
- University of California, Irvine, United States
- Duke University School of Medicine, United States
- Sam Houston State University, United States
- Houston Methodist Research Institute, United States
- 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.
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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.
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).
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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Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
eLife 8:e42988.
https://doi.org/10.7554/eLife.42988
