ArticlePLoS genetics2015
The role of the mammalian DNA end-processing enzyme polynucleotide kinase 3'-phosphatase in spinocerebellar ataxia type 3 pathogenesis.
Article in PLoS genetics, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 57 papers.
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Who cites it
57 citing papers in PubMed, 97 citations in OpenAlex.
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- Huntingtin preserves mitochondrial genome integrity in neurons, which is impaired in Huntington's disease.bioRxiv : the preprint server for biology · 2025Article
- Early transcriptomic perturbations highlight the spinal cord as a key pathogenic region in spinocerebellar ataxia type 3.Frontiers in cellular neuroscience · 2025Article
- Review
- ATXN3: a multifunctional protein involved in the polyglutamine disease spinocerebellar ataxia type 3.Expert reviews in molecular medicine · 2024Review
- Fructose-2,6-bisphosphate restores DNA repair activity of PNKP and ameliorates neurodegenerative symptoms in Huntington's disease.Proceedings of the National Academy of Sciences of the United States of America · 2024Article
- Fructose-2,6-bisphosphate restores DNA repair activity of PNKP and ameliorates neurodegenerative symptoms in Huntington's disease.bioRxiv : the preprint server for biology · 2024Article
- Site-specific acetylation of polynucleotide kinase 3'-phosphatase regulates its distinct role in DNA repair pathways.Nucleic acids research · 2024Article
- Oxidative Stress in Spinocerebellar Ataxia Type 3 and Its Attenuation by Herbal Remedies in Traditional Chinese Medicine: A Systematic Review.Antioxidants (Basel, Switzerland) · 2024Review
- Spinocerebellar ataxias: from pathogenesis to recent therapeutic advances.Frontiers in neuroscience · 2024Review
- Correction: The Role of the Mammalian DNA End-processing Enzyme Polynucleotide Kinase 3'-Phosphatase in Spinocerebellar Ataxia Type 3 Pathogenesis.PLoS genetics · 2024Article
- Article
- Highly Sensitive Radioactivity-Based DNA 3'-Phosphatase Activity Assay for Polynucleotide Kinase 3'-Phosphatase.Methods in molecular biology (Clifton, N.J.) · 2023Article
- Assays with Patient-Derived Organoids to Evaluate the Impact of Microbial Infection on Base Excision Repair (BER) Enzymes.Methods in molecular biology (Clifton, N.J.) · 2023Article
- CRISPR/Cas9 as a therapeutic tool for triple negative breast cancer: from bench to clinics.Frontiers in molecular biosciences · 2023Review
- The Josephin domain (JD) containing proteins are predicted to bind to the same interactors: Implications for spinocerebellar ataxia type 3 (SCA3) studies usingFrontiers in molecular neuroscience · 2023Article
- Article
- Transcription factor EB-mediated mesenchymal stem cell therapy induces autophagy and alleviates spinocerebellar ataxia type 3 defects in neuronal cells model.Cell death & disease · 2022Article
- DNA Double-Strand Breaks as Pathogenic Lesions in Neurological Disorders.International journal of molecular sciences · 2022Review
- Anti-Excitotoxic Effects of N-Butylidenephthalide Revealed by Chemically Insulted Purkinje Progenitor Cells Derived from SCA3 iPSCs.International journal of molecular sciences · 2022Article
Corrections and comments
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- Erratum issued
Authors and funding
17 authors at 5 institutions in 2 countries.
Funding
Abstract
DNA strand-breaks (SBs) with non-ligatable ends are generated by ionizing radiation, oxidative stress, various chemotherapeutic agents, and also as base excision repair (BER) intermediates. Several neurological diseases have already been identified as being due to a deficiency in DNA end-processing activities. Two common dirty ends, 3'-P and 5'-OH, are processed by mammalian polynucleotide kinase 3'-phosphatase (PNKP), a bifunctional enzyme with 3'-phosphatase and 5'-kinase activities. We have made the unexpected observation that PNKP stably associates with Ataxin-3 (ATXN3), a polyglutamine repeat-containing protein mutated in spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph Disease (MJD). This disease is one of the most common dominantly inherited ataxias worldwide; the defect in SCA3 is due to CAG repeat expansion (from the normal 14-41 to 55-82 repeats) in the ATXN3 coding region. However, how the expanded form gains its toxic function is still not clearly understood. Here we report that purified wild-type (WT) ATXN3 stimulates, and by contrast the mutant form specifically inhibits, PNKP's 3' phosphatase activity in vitro. ATXN3-deficient cells also show decreased PNKP activity. Furthermore, transgenic mice conditionally expressing the pathological form of human ATXN3 also showed decreased 3'-phosphatase activity of PNKP, mostly in the deep cerebellar nuclei, one of the most affected regions in MJD patients' brain. Finally, long amplicon quantitative PCR analysis of human MJD patients' brain samples showed a significant accumulation of DNA strand breaks. Our results thus indicate that the accumulation of DNA strand breaks due to functional deficiency of PNKP is etiologically linked to the pathogenesis of SCA3/MJD.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.