Department of Medical Chemistry, Faculty of Medicine, University of Debrecen, Egyetem Tér 1., 4032, Debrecen, Hungary.
Center of Excellence, The Hungarian Academy of Sciences, Budapest, Hungary.
Sci Rep. 2023 May 15;13(1):7869. doi: 10.1038/s41598-023-35076-w.
PARP2 is a member of the PARP enzyme family. Although, PARP2 plays role in DNA repair, it has regulatory roles in mitochondrial and lipid metabolism, it has pivotal role in bringing about the adverse effects of pharmacological PARP inhibitors. Previously, we showed that the ablation of PARP2 induces oxidative stress and, consequently, mitochondrial fragmentation. In attempt to identify the source of the reactive species we assessed the possible role of a central regulator of cellular antioxidant defense, nuclear factor erythroid 2-related factor 2 (NRF2). The silencing of PARP2 did not alter either the mRNA or the protein expression of NRF2, but changed its subcellular localization, decreasing the proportion of nuclear, active fraction of NRF2. Pharmacological inhibition of PARP2 partially restored the normal localization pattern of NRF2 and in line with that, we showed that NRF2 is PARylated that is absent in the cells in which PARP2 was silenced. Apparently, the PARylation of NRF2 by PARP2 has pivotal role in regulating the subcellular (nuclear) localization of NRF2. The silencing of PARP2 rearranged the expression of genes encoding proteins with antioxidant function, among these a subset of NRF2-dependent genes.
PARP2 是 PARP 酶家族的一员。尽管 PARP2 在 DNA 修复中发挥作用，但它在线粒体和脂质代谢中具有调节作用，在引起药理 PARP 抑制剂的不良反应方面起着关键作用。此前，我们表明 PARP2 的缺失会诱导氧化应激，进而导致线粒体碎片化。为了确定活性物质的来源，我们评估了细胞抗氧化防御的中央调节剂，即核红细胞 2 相关因子 2（NRF2）的可能作用。PARP2 的沉默既没有改变 NRF2 的 mRNA 也没有改变其蛋白表达，但改变了其亚细胞定位，减少了核内、NRF2 活性部分的比例。PARP2 的药理学抑制部分恢复了 NRF2 的正常定位模式，与此一致，我们表明 NRF2 被 PARP2 多聚化，而在 PARP2 沉默的细胞中不存在这种多聚化。显然，PARP2 对 NRF2 的 PAR 化在调节 NRF2 的亚细胞（核）定位方面起着关键作用。PARP2 的沉默重新排列了具有抗氧化功能的蛋白质编码基因的表达，其中包括一组 NRF2 依赖性基因。
