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

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.

Abnormal molecular signatures of inflammation, energy metabolism and vesicle biology in human Huntington disease peripheral tissues

“…2A). Alteration in protein sumoylation is a well described mechanism in HD, both for HTT itself, as well as in general [14-18]. Also, REST has been implicated in HD pathogenesis [19-21].…”

“…2A). Alteration in protein sumoylation is a well described mechanism in HD, both for HTT itself, as well as in general [14][15][16][17][18].…”

Influence of Sox protein SUMOylation on neural development and regeneration

“…Unlike the process of ubiqitination leading to protein degradation (Schmidt et al, 2021), SUMOylation, a PTM which attaches SUMO to a lysine residue of protein, does not lead to protein degradation (Savare et al, 2005), and is broadly studied in plants (Augustine and Vierstra, 2018), fruit flies (Nie et al, 2009;Koltun et al, 2017) and frogs (Bertke et al, 2019). There are three enzymatic activities that contribute to the SUMOylation process including E1 SUMO1 activating enzyme subunit 1/2 (Lois and Lima, 2005), E2 ubiquitin conjugating enzyme (Reverter and Lima, 2005), and E3 ligases such as RNA binding protein 2 and protein inhibitor of activated STAT1 (PIAS1) (Morozko et al, 2021). These E3 ligases mainly target the SUMO acceptor lysine within a ΨKXE motif (Ψ is any hydrophobic amino acid and X is any amino acid).…”

PIAS1 Regulates Hepatitis C Virus-Induced Lipid Droplet Accumulation by Controlling Septin 9 and Microtubule Filament Assembly

“…In yeast, septins were among the first proteins reported as being modified by SUMOylation [ 46 , 47 ], a process mediated by yeast Siz proteins, which are homologous with the mammalian protein inhibitor of activated STAT1 (PIAS1) [ 48 ]. The PIAS family of proteins consists of four members: PIAS1, PIAS2 (PIASx), PIAS3, and PIASy (PIAS4), which mainly function as small ubiquitin-like modifier (SUMO) E3 ligases, regulating the function of numerous transcription factors and hence diverse cellular processes, including cell proliferation [ 49 ], DNA damage responses [ 50 , 51 ], and inflammation responses [ 52 , 53 , 54 ]. In mammals, the critical role of SUMO modification of the specific septins 6, 7, and 11 in septin filament formation and cell division has been reported.…”