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

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

doi:10.1073/pnas.2021836118

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

Proc Natl Acad Sci U S A. 2021 Jan 26;118(4):e2021836118. doi: 10.1073/pnas.2021836118.

Authors

Eva L Morozko¹, Charlene Smith-Geater², Alejandro Mas Monteys³, Subrata Pradhan⁴, Ryan G Lim⁵, Peter Langfelder⁶, Marketta Kachemov¹, Jayesh A Kulkarni⁷, Josh Zaifman⁸, Austin Hill⁹, Jennifer T Stocksdale¹, Pieter R Cullis^{7

10}, Jie Wu¹¹, Joseph Ochaba¹, Ricardo Miramontes⁵, Anirban Chakraborty¹², Tapas K Hazra¹², Alice Lau², Sophie St-Cyr³, Iliana Orellana¹³, Lexi Kopan², Keona Q Wang², Sylvia Yeung⁵, Blair R Leavitt¹⁴, Jack C Reidling⁵, X William Yang¹⁵, Joan S Steffan^{2

5}, Beverly L Davidson^{3

16}, Partha S Sarkar^{4

17}, Leslie M Thompson^{18

2

5

11

13}

Affiliations

¹ Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
² Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
³ Raymond G. Perelman Center for Cell and Molecular Therapeutics, The Children's Hospital of Philadelphia, Philadelphia, PA 19104.
⁴ Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555.
⁵ Institute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697.
⁶ Department of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, CA 90095.
⁷ Department of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
⁸ Department of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1.
⁹ Incisive Genetics Inc., Vancouver, BC, Canada V6A 0H9.
¹⁰ NanoMedicines Innovation Network, University of British Columbia, Vancouver, BC, Canada V6T 1Z3.
¹¹ Department of Biological Chemistry, University of California, Irvine, CA 92697.
¹² Department of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555.
¹³ Sue and Bill Gross Stem Cell Institute, University of California, Irvine, CA 92697.
¹⁴ Centre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4.
¹⁵ Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095.
¹⁶ Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104.
¹⁷ Department of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555.
¹⁸ Department of Neurobiology and Behavior, University of California, Irvine, CA 92697; lmthomps@uci.edu.

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.

Keywords: DNA damage repair; Huntington's disease; PIAS; PNKP; SUMO.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Animals
Cell Differentiation
DNA / genetics*
DNA / metabolism
DNA Damage
DNA Repair Enzymes / genetics*
DNA Repair Enzymes / metabolism
DNA Repair*
Disease Models, Animal
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

Substances

HTT protein, human
Huntingtin Protein
PIAS1 protein, human
Protein Inhibitors of Activated STAT
RNA, Small Interfering
Small Ubiquitin-Related Modifier Proteins
DNA
PNKP protein, human
Phosphotransferases (Alcohol Group Acceptor)
DNA Repair Enzymes

Abstract

Publication types

MeSH terms

Substances

Grants and funding