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PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington's disease.
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.
Afiliação
  • Morozko EL; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
  • Smith-Geater C; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
  • Monteys AM; Raymond G. Perelman Center for Cell and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
  • Pradhan S; Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555.
  • Lim RG; Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697.
  • Langfelder P; Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, CA 90095.
  • Kachemov M; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
  • Kulkarni JA; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
  • Zaifman J; Department of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1.
  • Hill A; Incisive Genetics Inc., Vancouver, BC, Canada V6A 0H9.
  • Stocksdale JT; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
  • Cullis PR; Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
  • Wu J; NanoMedicines Innovation Network, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
  • Ochaba J; Department of Biological Chemistry, University of California, Irvine, CA 92697.
  • Miramontes R; Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
  • Chakraborty A; Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697.
  • Hazra TK; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
  • Lau A; Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
  • St-Cyr S; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
  • Orellana I; Raymond G. Perelman Center for Cell and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
  • Kopan L; Sue and Bill Gross Stem Cell Institute, University of California, Irvine, CA 92697.
  • Wang KQ; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
  • Yeung S; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
  • Leavitt BR; Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697.
  • Reidling JC; Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4.
  • Yang XW; Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697.
  • Steffan JS; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095.
  • Davidson BL; Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
  • Sarkar PS; Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697.
  • Thompson LM; Raymond G. Perelman Center for Cell and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
Proc Natl Acad Sci U S A ; 118(4)2021 01 26.
Article em En | MEDLINE | ID: mdl-33468657
ABSTRACT
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.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Processamento de Proteína Pós-Traducional / Doença de Huntington / Fosfotransferases (Aceptor do Grupo Álcool) / Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina / Enzimas Reparadoras do DNA / Reparo do DNA / Proteínas Inibidoras de STAT Ativados / Proteína Huntingtina Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2021 Tipo de documento: Article
Texto completo
Imprimir
XML
PubMed Links
Buscar no Google

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: DNA / Processamento de Proteína Pós-Traducional / Doença de Huntington / Fosfotransferases (Aceptor do Grupo Álcool) / Proteínas Modificadoras Pequenas Relacionadas à Ubiquitina / Enzimas Reparadoras do DNA / Reparo do DNA / Proteínas Inibidoras de STAT Ativados / Proteína Huntingtina Tipo de estudo: Prognostic_studies Limite: Animals / Female / Humans / Male Idioma: En Revista: Proc Natl Acad Sci U S A Ano de publicação: 2021 Tipo de documento: Article