PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease

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-deriv...

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Bibliographic Details
Published in:Proceedings of the National Academy of Sciences - PNAS 2021-01, Vol.118 (4)
Main Authors: Morozko, Eva L, Smith-Geater, Charlene, Monteys, Alejandro Mas, Pradhan, Subrata, Lim, Ryan G, Langfelder, Peter, Kachemov, Marketta, Kulkarni, Jayesh A, Zaifman, Josh, Hill, Austin, Stocksdale, Jennifer T, Cullis, Pieter R, Wu, Jie, Ochaba, Joseph, Miramontes, Ricardo, Chakraborty, Anirban, Hazra, Tapas K, Lau, Alice, St-Cyr, Sophie, Orellana, Iliana, Kopan, Lexi, Wang, Keona Q, Yeung, Sylvia, Leavitt, Blair R, Reidling, Jack C, Yang, X William, Steffan, Joan S, Davidson, Beverly L, Sarkar, Partha S, Thompson, Leslie M
Format: Article
Language:English
Subjects:
Animals
Biological Sciences
Cell Differentiation
Disease Models, Animal
DNA - genetics
DNA - metabolism
DNA Damage
DNA Repair
DNA Repair Enzymes - genetics
DNA Repair Enzymes - metabolism
Female
Humans
Huntingtin Protein - genetics
Huntingtin Protein - metabolism
Huntington Disease - genetics
Huntington Disease - metabolism
Huntington Disease - pathology
Male
Mice
Mice, Inbred C57BL
Mice, Transgenic
Neurons - metabolism
Neurons - pathology
Phosphotransferases (Alcohol Group Acceptor) - genetics
Phosphotransferases (Alcohol Group Acceptor) - metabolism
Pluripotent Stem Cells - metabolism
Pluripotent Stem Cells - pathology
Primary Cell Culture
Protein Inhibitors of Activated STAT - antagonists & inhibitors
Protein Inhibitors of Activated STAT - genetics
Protein Inhibitors of Activated STAT - metabolism
Protein Processing, Post-Translational
RNA, Small Interfering - genetics
RNA, Small Interfering - metabolism
Small Ubiquitin-Related Modifier Proteins - antagonists & inhibitors
Small Ubiquitin-Related Modifier Proteins - genetics
Small Ubiquitin-Related Modifier Proteins - metabolism
Sumoylation
Transcription, Genetic
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Summary: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.
ISSN:0027-8424
1091-6490
DOI:10.1073/pnas.2021836118