Correction NEUROSCIENCE Correction for “PIAS1 modulates striatal transcription, DNA Davidsonc,p, Partha S. Sarkard,q, and Leslie M. damage repair, and SUMOylation with relevance to Huntington’s Thompsona,b,e,k,m disease,” by Eva L. Morozko, Charlene Smith-Geater, Alejandro Mas Monteys, Subrata Pradhan, Ryan G. Lim, Peter Lang- aDepartment of Neurobiology and Behavior, University of California, Irvine, felder, Marketta Kachemov, Austin Hill, Jennifer T. Stocksdale, CA 92697; bDepartment of Psychiatry and Human Behavior, University of Pieter R. Cullis, Jie Wu, Joseph Ochaba, Ricardo Miramontes, California, Irvine, CA 92697; cRaymond G. Perelman Center for Cell and Anirban Chakraborty, Tapas K. Hazra, Alice Lau, Sophie St-cyr, Molecular Therapeutics, The Children’s Hospital of Philadelphia, d Iliana Orellana, Lexi Kopan, Keona Q. Wang, Sylvia Yeung, Philadelphia, PA 19104; Department of Neurology, University of Texas Medical Branch, Galveston, TX 77555; eInstitute of Memory Impairments and Blair R. Leavitt, Jack C. Reidling, X. William Yang, Joan S. Steffan, Neurological Disorders, University of California, Irvine, CA 92697; Beverly L. Davidson, Partha S. Sarkar, and Leslie M. Thompson, fDepartment of Human Genetics, David Geffen School of Medicine at which published January 19, 2021; 10.1073/pnas.2021836118 (Proc. University of California, Los Angeles, CA 90095; gDepartment of Natl. Acad. Sci. U.S.A. 118, e2021836118). Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3; hDepartment of Chemistry, University of The authors note that Jayesh A. Kulkarni and Josh Zaifman British Columbia, Vancouver, BC, Canada V6T 1Z1; iIncisive Genetics Inc., should be added to the author list between Marketta Kachemov Vancouver, BC, Canada V6A 0H9; jNanoMedicines Innovation Network, and Austin Hill. Jayesh A. Kulkarni should be credited with University of British Columbia, Vancouver, BC, Canada V6T 1Z3; kDepartment Contributed new reagents/analytical tools and Performed of Biological Chemistry, University of California, Irvine, CA 92697; lDepartment of Internal Medicine, University of Texas Medical Branch, Research. Josh Zaifman should be credited with Contributed Galveston, TX 77555; mSue and Bill Gross Stem Cell Institute, University new reagents/analytical tools and Performed Research. The of California, Irvine, CA 92697; nCentre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada CORRECTION corrected author line, affiliation line, and author contribu- o tions appear below. The online version has been corrected. V5Z 4H4; Center for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095; pDepartment of Pathology and Laboratory Medicine, Eva L. Morozkoa, Charlene Smith-Geaterb, Alejandro Mas University of Pennsylvania, Philadelphia, PA 19104; and qDepartment c d e of Neuroscience and Cell Biology, University of Texas Medical Branch, Monteys , Subrata Pradhan , Ryan G. Lim , Peter Galveston, TX 77555 Langfelderf, Marketta Kachemova, Jayesh A. Kulkarnig, Josh Zaifmanh, Austin Hilli, Jennifer T. Stocksdalea, Author contributions: E.L.M., C.S-G., A.M.M., B.R.L., J.C.R., B.L.D., P.S.S., Pieter R. Cullisg,j, Jie Wuk, Joseph Ochabaa, Ricardo and L.M.T. designed research; E.L.M., C.S-G., A.M.M., S.P., M.K., J.A.K., J.Z., e l l 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. Miramontes , Anirban Chakraborty , Tapas K. Hazra , performed research; J.A.K. and J.Z. contributed new reagents/analytical Alice Laub, Sophie St-cyrc, Iliana Orellanam, Lexi Kopanb, tools; 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. b e n analyzed data; E.L.M., C.S.-G., J.C.R., X.W.Y., J.S.S., and L.M.T. wrote the Keona Q. Wang , Sylvia Yeung , Blair R. Leavitt , Jack C. paper; and B.L.D., P.S.S., and L.M.T. provided resources and funding e o b,e Reidling , X. William Yang , Joan S. Steffan , Beverly L. acquisition. Published under the PNAS license. Published August 2, 2021. www.pnas.org/cgi/doi/10.1073/pnas.2112001118 PNAS 2021 Vol. 118 No. 32 e2112001118 https://doi.org/10.1073/pnas.2112001118 | 1of1 Downloaded by guest on October 1, 2021 PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease Eva L. Morozkoa,1, Charlene Smith-Geaterb,1, Alejandro Mas Monteysc, Subrata Pradhand, Ryan G. Lime, Peter Langfelderf, Marketta Kachemova, Jayesh A. Kulkarnig, Josh Zaifmanh, Austin Hilli, Jennifer T. Stocksdalea, Pieter R. Cullisg,j, Jie Wuk, Joseph Ochabaa, Ricardo Miramontese, Anirban Chakrabortyl, Tapas K. Hazral, Alice Laub, Sophie St-cyrc, Iliana Orellanam, Lexi Kopanb, Keona Q. Wangb, Sylvia Yeunge, Blair R. Leavittn, Jack C. Reidlinge, X. William Yango, Joan S. Steffanb,e, Beverly L. Davidsonc,p,2, Partha S. Sarkard,q,2, and Leslie M. Thompsona,b,e,k,m,2,3 aDepartment 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; gDepartment of Biochemistry and Molecular Biology, University of British Columbia, Vancouver, BC, Canada V6T 1Z3; hDepartment of Chemistry, University of British Columbia, Vancouver, BC, Canada V6T 1Z1; iIncisive Genetics Inc., Vancouver, BC, Canada V6A 0H9; jNanoMedicines Innovation Network, University of British Columbia, Vancouver, BC, Canada V6T 1Z3; kDepartment of Biological Chemistry, University of California, Irvine, CA 92697; lDepartment of Internal Medicine, University of Texas Medical Branch, Galveston, TX 77555; mSue and Bill Gross Stem Cell Institute, University of California, Irvine, CA 92697; nCentre for Molecular Medicine and Therapeutics, University of British Columbia, Vancouver, BC, Canada V5Z 4H4; oCenter for Neurobehavioral Genetics, Semel Institute for Neuroscience and Human Behavior, University of California, Los Angeles, CA 90095; pDepartment of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104; and qDepartment of Neuroscience and Cell Biology, University of Texas Medical Branch, Galveston, TX 77555 Edited by Stephen T. Warren, Emory University School of Medicine, Atlanta, GA, and approved December 14, 2020 (received for review October 26, 2020) DNA damage repair genes are modifiers of disease onset in SUMO modified (14) and identified Protein Inhibitor of Acti- Huntington’s disease (HD), but how this process intersects with vated STAT-1 (PIAS1) as an E3 SUMO ligase that enhances associated disease pathways remains unclear. Here we evaluated SUMOylation of HTT (15). Viral miRNA-mediated knockdown the mechanistic contributions of protein inhibitor of activated (KD) of Pias1 in R6/2 striata improved behavior and molecular NEUROSCIENCE STAT-1 (PIAS1) in HD mice and HD patient-derived induced plurip- readouts associated with HD progression (16). However, the otent stem cells (iPSCs) and find a link between PIAS1 and DNA precise mechanisms affected by PIAS1 in HD are not yet defined, damage repair pathways. We show that PIAS1 is a component of nor is the role of PIAS1 in neurons known. the transcription-coupled repair complex, that includes the DNA Here we evaluated the consequences of Pias1 reduction in a damage end processing enzyme polynucleotide kinase-phosphatase HD knockin mouse model which expresses the human expanded (PNKP), and that PIAS1 is a SUMO E3 ligase for PNKP. Pias1 knock- down (KD) in HD mice had a normalizing effect on HD transcrip- Significance tional dysregulation associated with synaptic function and disease- associated transcriptional coexpression modules enriched for DNA Genetic variants in genes involved in maintenance of genomic damage repair mechanisms as did reduction of PIAS1 in HD iPSC- stability are modifiers of Huntington’s disease (HD) age of onset. derived neurons. KD also restored mutant HTT-perturbed enzymatic This study shows a connection between the E3 SUMO ligase activity of PNKP and modulated genomic integrity of several tran- PIAS1, DNA damage repair protein PNKP, and HD-associated scriptionally normalized genes. The findings here now link SUMO transcriptional dysregulation. Reduction of Pias1 in a knockin modifying machinery to DNA damage repair responses and tran- HD mouse striatum normalizes disease-associated aberrant scriptional modulation in neurodegenerative disease. transcription, rescues perturbed enzymatic activity of Pnkp, and increases genomic integrity, while also having transcriptional DNA damage repair | SUMO | PIAS | Huntington’s disease | PNKP effects in WT animals. PIAS1 reduction in human iPSC neurons alters transcription of synaptic signaling and DNA damage re- ’ untington s disease (HD) is a devastating genetic neurode- pair, rescues PNKP activity, and increases genomic integrity in Hgenerative disease caused by an expanded CAG repeat HD iPSC-derived neurons. Finally, PIAS1 can modulate SUMO within the HD gene (HTT), which is translated into an expanded modification of PNKP, which is the first identification of an en- polyglutamine (PolyQ) repeat within the Huntingtin (HTT) zyme that regulates this modification. protein (1, 2). The size of the repeat expansion inversely corre- lates with age of onset in HD patients, with CAG-repeat length 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. de- accounting for about 50% of the observed age of onset (2, 3). signed research; E.L.M., C.S-G., A.M.M., S.P., M.K., J.A.K., J.Z., 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.