Skip to main content
Open Access Publications from the University of California

UC Irvine

UC Irvine Previously Published Works bannerUC Irvine

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

  • Author(s): Morozko, Eva L;
  • Smith-Geater, Charlene;
  • Monteys, Alejandro Mas;
  • Pradhan, Subrata;
  • Lim, Ryan G;
  • Langfelder, Peter;
  • Kachemov, Marketta;
  • Kulkarni, Jayesh A;
  • Zaifman, Josh;
  • Hill, Austin;
  • Stocksdale, Jennifer T;
  • Cullis, Pieter R;
  • Wu, Jie;
  • Ochaba, Joseph;
  • Miramontes, Ricardo;
  • Chakraborty, Anirban;
  • Hazra, Tapas K;
  • Lau, Alice;
  • St-Cyr, Sophie;
  • Orellana, Iliana;
  • Kopan, Lexi;
  • Wang, Keona Q;
  • Yeung, Sylvia;
  • Leavitt, Blair R;
  • Reidling, Jack C;
  • Yang, X William;
  • Steffan, Joan S;
  • Davidson, Beverly L;
  • Sarkar, Partha S;
  • Thompson, Leslie M
  • et al.

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.

Many UC-authored scholarly publications are freely available on this site because of the UC's open access policies. Let us know how this access is important for you.

Main Content
For improved accessibility of PDF content, download the file to your device.
Current View