TY - JOUR TI - PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease AU - Morozko, Eva L. AU - Smith-Geater, Charlene AU - Monteys, Alejandro Mas AU - Pradhan, Subrata AU - Lim, Ryan G. AU - Langfelder, Peter AU - Kachemov, Marketta AU - Hill, Austin AU - Stocksdale, Jennifer T. AU - Cullis, Pieter R. AU - Wu, Jie AU - Ochaba, Joseph AU - Miramontes, Ricardo AU - Chakraborty, Anirban AU - Hazra, Tapas K. AU - Lau, Alice AU - St-cyr, Sophie AU - Orellana, Iliana AU - Kopan, Lexi AU - Wang, Keona Q. AU - Yeung, Sylvia AU - Leavitt, Blair R. AU - Reidling, Jack C. AU - Yang, X. William AU - Steffan, Joan S. AU - Davidson, Beverly L. AU - Sarkar, Partha S. AU - Thompson, Leslie M. T2 - Proceedings of the National Academy of Sciences 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. Author Information Eva L. Morozkoa,1, Charlene Smith-Geaterb,1, Alejandro Mas Monteysc, Subrata Pradhand, Ryan G. Lime, Peter Langfelderf, Marketta Kachemova, Austin Hillg, Jennifer T. Stocksdalea, Pieter R. Cullish,i, Jie Wuj, Joseph Ochabaa, Ricardo Miramontese, Anirban Chakrabortyk, Tapas K. Hazrak, Alice Laub, Sophie St-cyrc, Iliana Orellanal, Lexi Kopanb, Keona Q. Wangb, Sylvia Yeunge, Blair R. Leavittm, Jack C. Reidlinge, X. William Yangn, Joan S. Steffanb,e, Beverly L. Davidsonc,o,2, Partha S. Sarkard,p,2, and Leslie M. Thompsona,b,e,j,l,2,3aDepartment of Neurobiology and Behavior, University of California, Irvine, CA 92697;bDepartment of Psychiatry and Human Behavior, University of California, Irvine, CA 92697;cRaymond G. Perelman Center for Cell and Molecular Therapeutics, The Children’s Hospital of Philadelphia, Philadelphia, PA 19104;dDepartment of Neurology, University of Texas Medical Branch, Galveston, TX 77555;eInstitute of Memory Impairments and Neurological Disorders, University of California, Irvine, CA 92697;fDepartment of Human Genetics, David Geffen School of Medicine at University of California, Los Angeles, CA 90095;gIncisive Genetics Inc., Vancouver, BC, Canada V6A 0H9;hNanoMedicines Innovation Network, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;iDepartment of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3;jDepartment of Biological Chemistry, University of California, Irvine, CA 92697;kDepartment of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555;lSue and Bill Gross Stem Cell Institute, University of California, Irvine, CA 92697;mCentre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4;nCenter for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095;oDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104;pDepartment of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555Edited by Stephen T. Warren, Emory University School of Medicine, Atlanta, GA, and approved December 14, 2020 (received for review October 26, 2020) Footnotes↵1E.L.M. and C.S.-G. contributed equally to this work.↵2B.L.D., P.S.S., and L.M.T. contributed equally to this work.↵3To whom correspondence may be addressed. Email: lmthomps@uci.edu.Author contributions: E.L.M., C.S-G., A.M.M., B.R.L., J.C.R., B.L.D., P.S.S., and L.M.T. designed research; E.L.M., C.S-G., A.M.M., S.P., M.K., A.H., J.T.S., P.R.C., J.O., A.C., T.K.H., A.L., S.S.-c., I.O., L.K., K.Q.W., and S.Y. performed research; E.L.M., C.S.-G., S.P., R.G.L., P.L., J.W., R.M., J.C.R., X.W.Y., and J.S.S. analyzed data; E.L.M., C.S.-G., J.C.R., X.W.Y., J.S.S., and L.M.T. wrote the paper; and B.L.D., P.S.S., and L.M.T. provided resources and funding acquisition.The authors declare no competing interest.This article is a PNAS Direct Submission.This article contains supporting information online at https://www.pnas.org/lookup/suppl/doi:10.1073/pnas.2021836118/-/DCSupplemental. DA - 2021/01/26/ PY - 2021 DO - 10.1073/pnas.2021836118 DP - www.pnas.org VL - 118 IS - 4 J2 - PNAS LA - en SN - 0027-8424, 1091-6490 UR - https://www.pnas.org/content/118/4/e2021836118 Y2 - 2021/01/19/22:35:02 KW - DNA damage repair KW - Huntington's disease KW - PIAS KW - PNKP KW - SUMO ER -