@article{9cefe14eae5548c3a250bd915e67cb05,
title = "PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington{\textquoteright}s disease",
abstract = "DNA damage repair genes are modifiers of disease onset in Huntington{\textquoteright}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{\textquoteright}s disease, PIAS, PNKP, SUMO",
author = "Morozko, {Eva L.} and Charlene Smith-Geater and Monteys, {Alejandro Mas} and Subrata Pradhan and Lim, {Ryan G.} and Peter Langfelder and Marketta Kachemov and Austin Hill and Stocksdale, {Jennifer T.} and Cullis, {Pieter R.} and Jie Wu and Joseph Ochaba and Ricardo Miramontes and Anirban Chakraborty and Hazra, {Tapas K.} and Alice Lau and Sophie St-Cyr and Iliana Orellana and Lexi Kopan and Wang, {Keona Q.} and Sylvia Yeung and Leavitt, {Blair R.} and Reidling, {Jack C.} and {William Yang}, X. and Steffan, {Joan S.} and Davidson, {Beverly L.} and Sarkar, {Partha S.} and Thompson, {Leslie M.}",
note = "Funding Information: ACKNOWLEDGMENTS. We thank Christopher Pearson for his valued insights and input for this study. Primary support was from NIH (NS090390 to L.M.T. and B.L.D.). Additional support was by NIH (NS072453 to J.S.S., NS076631 to B.L.D., NSO79541-01 and R01 EY026089-01A1 to P.S.S., U54 NS091046 NeuroLINCS center to L.M.T.), the Hereditary Disease Foundation (J.S.S. and C.S.-G.), CHDI Foundation (J.S.S.), The Roy J. Carver Trust and The Children{\textquoteright}s Hospital of Philadelphia Research Institute (B.L.D.), HD CARE (L.M.T.), and an NSF fellowship (E.L.M.). We thank the University of California, Irvine Institute for Memory Impairments and Neurological Disorders and the Optical Biology Shared Resource of the Cancer Center Support Grant (CA-62203) at the UCI for assistance in carrying out experiments. This work was possible, in part, through access to the Genomic High Throughput Facility Shared Resource of the Cancer Center Support Grant (CA-62203) at UCI. Funding Information: We thank Christopher Pearson for his valued insights and input for this study. Primary support was from NIH (NS090390 to L.M.T. and B.L.D.). Additional support was by NIH (NS072453 to J.S.S., NS076631 to B.L.D., NSO79541-01 and R01 EY026089-01A1 to P.S.S., U54 NS091046 NeuroLINCS center to L.M.T.), the Hereditary Disease Foundation (J.S.S. and C.S.-G.), CHDI Foundation (J.S.S.), The Roy J. Carver Trust and The Children{\textquoteright}s Hospital of Philadelphia Research Institute (B.L.D.), HD CARE (L.M.T.), and an NSF fellowship (E.L.M.). We thank the University of California, Irvine Institute for Memory Impairments and Neurological Disorders and the Optical Biology Shared Resource of the Cancer Center Support Grant (CA-62203) at the UCI for assistance in carrying out experiments. This work was possible, in part, through access to the Genomic High Throughput Facility Shared Resource of the Cancer Center Support Grant (CA-62203) at UCI. Publisher Copyright: {\textcopyright} 2021 National Academy of Sciences. All rights reserved.",
year = "2021",
month = jan,
day = "26",
doi = "10.1073/pnas.2021836118",
language = "English (US)",
volume = "118",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
publisher = "National Academy of Sciences",
number = "4",
}