Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription
| Autor: | Audrey S. Dickey, Subrata Pradhan, Jeffrey Snowden, Anirban Chakraborty, Kara L Gordon, Subo Yuan, Albert R. La Spada, Tapas K. Hazra, Lisa M. Ellerby, Partha S. Sarkar, Rui Gao, Leslie M. Thompson, Charlene Geater, Sanjeev Choudhary, Tetsuo Ashizawa |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2019 |
| Předmět: |
Huntingtin
DNA Repair Transcription Genetic Mouse Transcription-Coupled DNA Repair RNA polymerase II DNA damage response neuroscience chemistry.chemical_compound 0302 clinical medicine Ubiquitin Transcription (biology) Biology (General) Ataxin-3 0303 health sciences Huntingtin Protein biology Chemistry General Neuroscience Huntington's disease General Medicine DNA-Directed RNA Polymerases 3. Good health Cell biology Phosphotransferases (Alcohol Group Acceptor) Medicine Protein Binding Research Article congenital hereditary and neonatal diseases and abnormalities QH301-705.5 DNA repair DNA damage Science Sialoglycoproteins Mice Transgenic CREB General Biochemistry Genetics and Molecular Biology Cell Line 03 medical and health sciences Animals Humans mouse 030304 developmental biology General Immunology and Microbiology Peptide Fragments Repressor Proteins DNA Repair Enzymes biology.protein Mutant Proteins Protein Multimerization polyglutamine 030217 neurology & neurosurgery DNA Neuroscience |
| Zdroj: | Gao, Rui; Chakraborty, Anirban; Geater, Charlene; Pradhan, Subrata; Gordon, Kara L; Snowden, Jeffrey; et al.(2019). Mutant huntingtin impairs PNKP and ATXN3, disrupting DNA repair and transcription.. eLife, 8. doi: 10.7554/eLife.42988. UC Irvine: Retrieved from: http://www.escholarship.org/uc/item/6qw59090 eLife eLife, Vol 8 (2019) |
| Popis: | 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. eLife digest Our DNA encodes the instructions to make proteins, which then go on to perform many crucial roles in the cell. Breakages and damage to DNA occur over time, and if uncorrected, they can make the instructions illegible or incorrect. A build-up of damages can be harmful – for example, DNA damage from excessive UV light exposure can cause skin cancer. Luckily, cells contain DNA repair complexes, protein machines that surveil DNA and correct errors or breakages. An accumulation of DNA breakages is thought to contribute to the development of Huntington’s disease, a devastating and currently incurable condition where brain cells slowly die. The immediate cause of Huntington’s disease is well known: Huntington’s patients have an abnormal, mutant version of a protein called huntingtin. However, it is still unclear how the mutant huntingtin causes the symptoms of the disease and participates in cell death. Gao et al. carefully studied the proteins that huntingtin physically interacts with. The experiments revealed that huntingtin is part of a newly identified DNA repair complex that fixes breakages in DNA as the molecule is ‘read’ by the cell. The presence of the normal huntingtin protein promoted DNA repair. However, when the healthy huntingtin was replaced with the mutant version found in Huntington’s disease, the activity of the DNA repair complex was greatly reduced. This resulted in a build-up of DNA errors, triggering a series of events that ultimately led to cell death. In addition, in mice engineered to produce the mutant version of huntingtin, the accumulation of DNA damage was particularly important in two brain regions that are severely damaged in patients with Huntington’s disease. There is currently no effective treatment for Huntington’s disease. However, understanding how the mutant huntingtin damages brain cells may provide new targets for future therapies. More broadly, several other brain disorders share similarities with Huntington’s disease, and it remains to be seen whether the same mechanisms could be at work in all these conditions. |
| Databáze: | OpenAIRE |
| Externí odkaz: |
|