Department of Neurology, Duke University School of Medicine, Durham, United States
Leslie M Thompson
Department of Psychiatry and Human Behavior and the Sue and Bill Gross Stem Cell Center, University of California, Irvine, Irvine, United States; Department of Neurobiology and Behavior, University of California, Irvine, Institute for Memory Impairments and Neurological Disorders, Irvine, United States
Tapas K Hazra
Department of Internal Medicine, University of Texas Medical Branch, Galveston, United States
Department of Neurology, University of Texas Medical Branch, Galveston, United States; Department of Neuroscience, Cell Biology and Anatomy, University of Texas Medical Branch, Galveston, United States
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.
