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; 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

Eva L. Morozko, Charlene Smith-Geater, Alejandro Mas Monteys, Subrata Pradhan, Ryan G. Lim, Peter Langfelder, Marketta Kachemov, 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. WangSylvia Yeung, Blair R. Leavitt, Jack C. Reidling, X. William Yang, Joan S. Steffan, Beverly L. Davidson, Partha S. Sarkar, Leslie M. Thompson

Research output: Contribution to journal › Article › peer-review

34 Scopus citations

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.

Original language	English (US)
Article number	e2021836118
Journal	Proceedings of the National Academy of Sciences of the United States of America
Volume	118
Issue number	4
DOIs	https://doi.org/10.1073/pnas.2021836118
State	Published - Jan 26 2021
Externally published	Yes

Keywords

DNA damage repair
Huntington’s disease
PIAS
PNKP
SUMO

ASJC Scopus subject areas

General

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10.1073/pnas.2021836118

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Morozko, E. L., Smith-Geater, C., Monteys, A. M., Pradhan, S., Lim, R. G., Langfelder, P., Kachemov, M., Hill, A., Stocksdale, J. T., Cullis, P. R., Wu, J., Ochaba, J., Miramontes, R., Chakraborty, A., Hazra, T. K., Lau, A., St-Cyr, S., Orellana, I., Kopan, L., ... Thompson, L. M. (2021). PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease. Proceedings of the National Academy of Sciences of the United States of America, 118(4), Article e2021836118. https://doi.org/10.1073/pnas.2021836118

PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease. / Morozko, Eva L.; Smith-Geater, Charlene; Monteys, Alejandro Mas et al.
In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 118, No. 4, e2021836118, 26.01.2021.

Research output: Contribution to journal › Article › peer-review

Morozko, EL, Smith-Geater, C, Monteys, AM, Pradhan, S, Lim, RG, Langfelder, P, Kachemov, M, Hill, A, Stocksdale, JT, Cullis, PR, Wu, J, Ochaba, J, Miramontes, R, Chakraborty, A, Hazra, TK, Lau, A, St-Cyr, S, Orellana, I, Kopan, L, Wang, KQ, Yeung, S, Leavitt, BR, Reidling, JC, William Yang, X, Steffan, JS, Davidson, BL, Sarkar, PS & Thompson, LM 2021, 'PIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease', Proceedings of the National Academy of Sciences of the United States of America, vol. 118, no. 4, e2021836118. https://doi.org/10.1073/pnas.2021836118

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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.",

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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 - William Yang, X.

AU - Steffan, Joan S.

AU - Davidson, Beverly L.

AU - Sarkar, Partha S.

AU - Thompson, Leslie M.

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N2 - 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.

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.

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KW - Huntington’s disease

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KW - SUMO

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

Abstract

Keywords

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