Open AccessPIAS1 modulates striatal transcription, DNA damage repair, and SUMOylation with relevance to Huntington’s disease
Author(s) -
Eva L. Morozko,
Charlene Smith-Geater,
Alejandro Mas Monteys,
Subrata Pradhan,
Ryan G. Lim,
Peter Langfelder,
Marketta Kachemov,
Austin Hill,
Jennifer 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 Y. Yeung,
Blair R. Leavitt,
Jack C. Reidling,
Xiangdong Yang,
Joan S. Steffan,
Beverly L. Davidson,
Partha S. Sarkar,
Leslie Thompson
Publication year - 2021
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.2021836118
Subject(s) - huntington's disease , dna repair , biology , transcription (linguistics) , dna damage , microbiology and biotechnology , transcription factor , ubiquitin ligase , genetics , gene , dna , ubiquitin , disease , medicine , linguistics , philosophy
Significance Genetic variants in genes involved in maintenance of genomic stability are modifiers of Huntington’s disease (HD) age of onset. This study shows a connection between the E3 SUMO ligase PIAS1, DNA damage repair protein PNKP, and HD-associated transcriptional dysregulation. Reduction of Pias1 in a knockin HD mouse striatum normalizes disease-associated aberrant transcription, rescues perturbed enzymatic activity of Pnkp, and increases genomic integrity, while also having transcriptional effects in WT animals. PIAS1 reduction in human iPSC neurons alters transcription of synaptic signaling and DNA damage repair, rescues PNKP activity, and increases genomic integrity in HD iPSC-derived neurons. Finally, PIAS1 can modulate SUMO modification of PNKP, which is the first identification of an enzyme that regulates this modification.