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.
Data availability
All data generated are included in the manuscript and supporting files.
Article and author information
Author details
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).
Reviewing Editor
- Harry T Orr, University of Minnesota, United States
Publication history
- Received: October 19, 2018
- Accepted: April 16, 2019
- Accepted Manuscript published: April 17, 2019 (version 1)
- 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.
Metrics
-
- 3,436
- Page views
-
- 757
- Downloads
-
- 55
- Citations
Article citation count generated by polling the highest count across the following sources: Scopus, Crossref, PubMed Central.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
eLife 8:e42988.
https://doi.org/10.7554/eLife.42988
Further reading
-
- Neuroscience
Artificial neural networks could pave the way for efficiently simulating large-scale models of neuronal networks in the nervous system.
-
- Neuroscience
A key question in decision making is how humans arbitrate between competing learning and memory systems to maximize reward. We address this question by probing the balance between the effects, on choice, of incremental trial-and-error learning versus episodic memories of individual events. Although a rich literature has studied incremental learning in isolation, the role of episodic memory in decision making has only recently drawn focus, and little research disentangles their separate contributions. We hypothesized that the brain arbitrates rationally between these two systems, relying on each in circumstances to which it is most suited, as indicated by uncertainty. We tested this hypothesis by directly contrasting contributions of episodic and incremental influence to decisions, while manipulating the relative uncertainty of incremental learning using a well-established manipulation of reward volatility. Across two large, independent samples of young adults, participants traded these influences off rationally, depending more on episodic information when incremental summaries were more uncertain. These results support the proposal that the brain optimizes the balance between different forms of learning and memory according to their relative uncertainties and elucidate the circumstances under which episodic memory informs decisions.
