PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease
| العنوان: | PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease |
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| المؤلفون: | Eva L. Morozko, Charlene Smith-Geater, Alejandro Mas Monteys, Subrata Pradhan, Ryan G. Lim, Peter Langfelder, Marketta Kachemov, Jayesh A. Kulkarni, Josh Zaifman, Austin Hill, Jennifer T. Stocksdale, Pieter R. Cullis, Jie Wu, Joseph Ochaba, Ricardo Miramontes, Anirban Chakraborty, Tapas K. Hazra, Alice Lau, Sophie St-cyr, Iliana Orellana, Lexi Kopan, Keona Q. Wang, Sylvia Yeung, Blair R. Leavitt, Jack C. Reidling, X. William Yang, Joan S. Steffan, Beverly L. Davidson, Partha S. Sarkar, Leslie M. Thompson |
| المصدر: | Proc Natl Acad Sci U S A Proceedings of the National Academy of Sciences of the United States of America, vol 118, iss 4 |
| سنة النشر: | 2021 |
| مصطلحات موضوعية: | Huntington's Disease, 0301 basic medicine, Male, DNA Repair, Transcription, Genetic, Mutant, SUMO protein, Neurodegenerative, Inbred C57BL, Transgenic, Mice, 0302 clinical medicine, DNA damage repair, 2.1 Biological and endogenous factors, Aetiology, RNA, Small Interfering, Induced pluripotent stem cell, Neurons, Gene knockdown, Huntingtin Protein, Multidisciplinary, Cell Differentiation, Protein Inhibitors of Activated STAT, Ubiquitin ligase, Cell biology, Phosphotransferases (Alcohol Group Acceptor), Huntington Disease, Neurological, Small Ubiquitin-Related Modifier Proteins, Female, Transcription, Pluripotent Stem Cells, PIAS, DNA damage, 1.1 Normal biological development and functioning, Primary Cell Culture, Mice, Transgenic, Biology, Small Interfering, 03 medical and health sciences, Rare Diseases, Genetic, Huntington's disease, Underpinning research, Genetics, medicine, Animals, Humans, PNKP, Gene, Protein Processing, Animal, Post-Translational, Neurosciences, Sumoylation, Correction, DNA, Stem Cell Research, medicine.disease, Brain Disorders, Mice, Inbred C57BL, Disease Models, Animal, 030104 developmental biology, DNA Repair Enzymes, SUMO, Disease Models, biology.protein, RNA, Protein Processing, Post-Translational, 030217 neurology & neurosurgery, DNA Damage |
| الوصف: | DNA damage repair genes are modifiers of disease onset in Huntington's disease (HD), but how this process intersects with associated disease pathways remains unclear. Here we evaluated the mechanistic contributions of protein inhibitor of activated STAT-1 (PIAS1) in HD mice and HD patient-derived induced pluripotent stem cells (iPSCs) and find a link between PIAS1 and DNA damage repair pathways. We show that PIAS1 is a component of the transcription-coupled repair complex, that includes the DNA damage end processing enzyme polynucleotide kinase-phosphatase (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knockdown (KD) in HD mice had a normalizing effect on HD transcriptional dysregulation associated with synaptic function and disease-associated transcriptional coexpression modules enriched for DNA damage repair mechanisms as did reduction of PIAS1 in HD iPSC-derived neurons. KD also restored mutant HTT-perturbed enzymatic activity of PNKP and modulated genomic integrity of several transcriptionally normalized genes. The findings here now link SUMO modifying machinery to DNA damage repair responses and transcriptional modulation in neurodegenerative disease. |
| وصف الملف: | application/pdf |
| تدمد: | 1091-6490 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::e38249a9a6accb8170577dc07adbd259Test https://pubmed.ncbi.nlm.nih.gov/34341126Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....e38249a9a6accb8170577dc07adbd259 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 10916490 |
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