PARP2 poly(ADP-ribosyl)ates nuclear factor erythroid 2-related factor 2 (NRF2) affecting NRF2 subcellular localization

Abstract

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.

Specific and shared biological functions of PARP2 – is PARP2 really a lil’ brother of PARP1?

“…In accordance with that, while the silencing of PARP2 increased the cytosolic fraction of NRF2 and led to the rearrangement of the expression of numerous genes associated with redox homoeostasis (Ref. 95). Silencing, inhibition or deletion of PARP1 was also reported to induce oxidative stress (Ref.…”

“…PARP2 has multiple PARylation targets including proteins involved in transcription, translation, mitochondrial organization, redox balance, DNA repair, PARylation machinery (e.g. HPF1) ( Refs 53,56,94,95,96,97,98,99). Nucleic acid structures may also be sites of ADP-ribosylation (Ref.…”

“…Genes whose expression changes in the absence of PARP2 are involved in intermediary metabolism (mitochondrial, carbohydrate, fatty acid and cholesterol/steroid metabolism) ( Refs 11,18,25,67,84,85,151,152,155), redox balance (Ref. 95) or inflammation (Ref. 89).…”

“…181) and the impaired capacity for scavenging ROS (Ref. 95). Impaired ROS scavenging is, at least in part, due to the PAR-mediated cellular relocalization of nuclear factor erythroid 2 (NFE2)-related factor 2 (NFE2L2, or NRF2).…”

“…PARylated NRF2 is anchored to the nucleus (Ref. 95). In accordance with that, while the silencing of PARP2 increased the cytosolic fraction of NRF2 and led to the rearrangement of the expression of numerous genes associated with redox homoeostasis (Ref.…”