PMID- 33468657 OWN - NLM STAT- MEDLINE DCOM- 20210609 LR - 20240330 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 4 DP - 2021 Jan 26 TI - PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease. LID - 10.1073/pnas.2021836118 [doi] LID - e2021836118 AB - 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. CI - Copyright (c) 2021 the Author(s). Published by PNAS. FAU - Morozko, Eva L AU - Morozko EL AD - Department of Neurobiology and Behavior, University of California, Irvine, CA 92697. FAU - Smith-Geater, Charlene AU - Smith-Geater C AUID- ORCID: 0000-0003-2136-4420 AD - Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697. FAU - Monteys, Alejandro Mas AU - Monteys AM AD - Raymond G. Perelman Center for Cell and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104. FAU - Pradhan, Subrata AU - Pradhan S AUID- ORCID: 0000-0002-3636-2615 AD - Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Lim, Ryan G AU - Lim RG AUID- ORCID: 0000-0001-6388-5158 AD - Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697. FAU - Langfelder, Peter AU - Langfelder P AUID- ORCID: 0000-0003-3418-4146 AD - Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, CA 90095. FAU - Kachemov, Marketta AU - Kachemov M AUID- ORCID: 0000-0001-7954-8930 AD - Department of Neurobiology and Behavior, University of California, Irvine, CA 92697. FAU - Kulkarni, Jayesh A AU - Kulkarni JA AD - Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. FAU - Zaifman, Josh AU - Zaifman J AD - Department of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1. FAU - Hill, Austin AU - Hill A AD - Incisive Genetics Inc., Vancouver, BC, Canada V6A 0H9. FAU - Stocksdale, Jennifer T AU - Stocksdale JT AUID- ORCID: 0000-0002-4304-6266 AD - Department of Neurobiology and Behavior, University of California, Irvine, CA 92697. FAU - Cullis, Pieter R AU - Cullis PR AUID- ORCID: 0000-0001-9586-2508 AD - Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. AD - NanoMedicines Innovation Network, University of British Columbia, Vancouver, BC, Canada V6T 1Z3. FAU - Wu, Jie AU - Wu J AD - Department of Biological Chemistry, University of California, Irvine, CA 92697. FAU - Ochaba, Joseph AU - Ochaba J AD - Department of Neurobiology and Behavior, University of California, Irvine, CA 92697. FAU - Miramontes, Ricardo AU - Miramontes R AD - Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697. FAU - Chakraborty, Anirban AU - Chakraborty A AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555. FAU - Hazra, Tapas K AU - Hazra TK AD - Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555. FAU - Lau, Alice AU - Lau A AD - Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697. FAU - St-Cyr, Sophie AU - St-Cyr S AUID- ORCID: 0000-0003-2448-9202 AD - Raymond G. Perelman Center for Cell and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104. FAU - Orellana, Iliana AU - Orellana I AD - Sue and Bill Gross Stem Cell Institute, University of California, Irvine, CA 92697. FAU - Kopan, Lexi AU - Kopan L AD - Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697. FAU - Wang, Keona Q AU - Wang KQ AUID- ORCID: 0000-0002-7715-2489 AD - Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697. FAU - Yeung, Sylvia AU - Yeung S AD - Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697. FAU - Leavitt, Blair R AU - Leavitt BR AD - Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4. FAU - Reidling, Jack C AU - Reidling JC AD - Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697. FAU - Yang, X William AU - Yang XW AD - Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095. FAU - Steffan, Joan S AU - Steffan JS AUID- ORCID: 0000-0003-2467-6294 AD - Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697. AD - Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697. FAU - Davidson, Beverly L AU - Davidson BL AD - Raymond G. Perelman Center for Cell and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104. AD - Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104. FAU - Sarkar, Partha S AU - Sarkar PS AD - Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555. AD - Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555. FAU - Thompson, Leslie M AU - Thompson LM AD - Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; lmthomps@uci.edu. AD - Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697. AD - Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697. AD - Department of Biological Chemistry, University of California, Irvine, CA 92697. AD - Sue and Bill Gross Stem Cell Institute, University of California, Irvine, CA 92697. LA - eng GR - R01 NS113612/NS/NINDS NIH HHS/United States GR - R01 EY026089/EY/NEI NIH HHS/United States GR - R56 NS072453/NS/NINDS NIH HHS/United States GR - R01 NS076631/NS/NINDS NIH HHS/United States GR - P30 CA062203/CA/NCI NIH HHS/United States GR - U54 NS091046/NS/NINDS NIH HHS/United States GR - R01 NS090390/NS/NINDS NIH HHS/United States GR - R56 NS090390/NS/NINDS NIH HHS/United States GR - R01 NS072453/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (HTT protein, human) RN - 0 (Huntingtin Protein) RN - 0 (PIAS1 protein, human) RN - 0 (Protein Inhibitors of Activated STAT) RN - 0 (RNA, Small Interfering) RN - 0 (Small Ubiquitin-Related Modifier Proteins) RN - 9007-49-2 (DNA) RN - EC 2.7.1.- (PNKP protein, human) RN - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor)) RN - EC 6.5.1.- (DNA Repair Enzymes) SB - IM EIN - Proc Natl Acad Sci U S A. 2021 Aug 10;118(32):. PMID: 34341126 MH - Animals MH - Cell Differentiation MH - DNA/*genetics/metabolism MH - DNA Damage MH - *DNA Repair MH - DNA Repair Enzymes/*genetics/metabolism MH - Disease Models, Animal MH - Female MH - Humans MH - Huntingtin Protein/*genetics/metabolism MH - Huntington Disease/*genetics/metabolism/pathology MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Mice, Transgenic MH - Neurons/metabolism/pathology MH - Phosphotransferases (Alcohol Group Acceptor)/*genetics/metabolism MH - Pluripotent Stem Cells/metabolism/pathology MH - Primary Cell Culture MH - Protein Inhibitors of Activated STAT/antagonists & inhibitors/*genetics/metabolism MH - *Protein Processing, Post-Translational MH - RNA, Small Interfering/genetics/metabolism MH - Small Ubiquitin-Related Modifier Proteins/antagonists & inhibitors/*genetics/metabolism MH - Sumoylation MH - Transcription, Genetic PMC - PMC7848703 OTO - NOTNLM OT - DNA damage repair OT - Huntington's disease OT - PIAS OT - PNKP OT - SUMO COIS- The authors declare no competing interest. EDAT- 2021/01/21 06:00 MHDA- 2021/06/10 06:00 PMCR- 2021/01/18 CRDT- 2021/01/20 05:43 PHST- 2021/01/20 05:43 [entrez] PHST- 2021/01/21 06:00 [pubmed] PHST- 2021/06/10 06:00 [medline] PHST- 2021/01/18 00:00 [pmc-release] AID - 2021836118 [pii] AID - 202021836 [pii] AID - 10.1073/pnas.2021836118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Jan 26;118(4):e2021836118. doi: 10.1073/pnas.2021836118.