Department of Neurobiology and Behavior, University of California, Irvine, CA 92697.
Department of Psychiatry and Human Behavior, University of California, Irvine, CA 92697.
Proc Natl Acad Sci U S A. 2021 Jan 26;118(4). doi: 10.1073/pnas.2021836118.
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.
DNA 损伤修复基因是亨廷顿病 (HD) 发病的修饰因子，但这一过程如何与相关疾病途径交叉仍不清楚。在这里，我们评估了蛋白抑制剂 of activated STAT-1 (PIAS1) 在 HD 小鼠和 HD 患者来源的诱导多能干细胞 (iPSC) 中的作用机制，并发现了 PIAS1 与 DNA 损伤修复途径之间的联系。我们表明，PIAS1 是转录偶联修复复合物的一个组成部分，该复合物包括 DNA 损伤末端加工酶多核苷酸激酶磷酸酶 (PNKP)，并且 PIAS1 是 PNKP 的 SUMO E3 连接酶。在 HD 小鼠中敲低 PIAS1 (KD) 对与突触功能相关的 HD 转录失调具有正常化作用，与 DNA 损伤修复机制相关的疾病相关转录共表达模块也具有正常化作用，而在 HD iPSC 衍生神经元中降低 PIAS1 也具有正常化作用。KD 还恢复了突变 HTT 扰乱的 PNKP 酶活性，并调节了几个转录正常化基因的基因组完整性。这里的发现现在将 SUMO 修饰机制与神经退行性疾病中的 DNA 损伤修复反应和转录调节联系起来。
