Parp3 promotes astrocytic differentiation through a tight regulation of Nox4-induced ROS and mTorc2 activation

Abstract

Parp3 is a member of the Poly(ADP-ribose) polymerase (Parp) family that has been characterized for its functions in strand break repair, chromosomal rearrangements, mitotic segregation and tumor aggressiveness. Yet its physiological implications remain unknown. Here we report a central function of Parp3 in the regulation of redox homeostasis in continuous neurogenesis in mice. We show that the absence of Parp3 provokes Nox4-induced oxidative stress and defective mTorc2 activation leading to inefficient differentiation of post-natal neural stem/progenitor cells to astrocytes. The accumulation of ROS contributes to the decreased activity of mTorc2 as a result of an oxidation-induced and Fbxw7-mediated ubiquitination and degradation of Rictor. In vivo, mTorc2 signaling is compromised in the striatum of naïve post-natal Parp3-deficient mice and 6 h after acute hypoxia-ischemia. These findings reveal a physiological function of Parp3 in the tight regulation of striatal oxidative stress and mTorc2 during astrocytic differentiation and in the acute phase of hypoxia-ischemia.

Silencing of Poly(ADP-Ribose) Polymerase-2 Induces Mitochondrial Reactive Species Production and Mitochondrial Fragmentation

“…PARP1 and PARP3 were implicated in regulating mitochondrial morphology [20,85,86]; hence, we assessed the possible involvement of PARP1 and PARP3. Silencing PARP1 in scPARP2 and shPARP2 C2C12 cells (Figure 11A) led to the loss of PARP1 auto-PARylation (Figure 11A).…”

Fall of Parp3 restrains Lgr5+ stem cells proliferation and mucosal renovation in intestinal aging

“…Poly (ADP-ribose) polymerase 3 (Parp3) is a member of ARTD (Parp) family which can synthesize poly (ADP-ribose) at the expense of NAD + [30]. Previous studies showed that Parp3 was involved in the cellular response to DNA damage [31], mitotic progression [32], chromosomal rearrangements [33], the regulation of redox homeostasis [34] and tumor aggressiveness [35]. Moreover, Parp3 inhibitor ME0328 was found to cause cell cycle arrest in breast cancer cells [36].…”

PARP12 is required for mitochondrial function maintenance in thermogenic adipocytes

“…Thus, identifying the PARP12-interacting mitochondrial proteins would help us to understand the underlying mechanisms. Some pathways that are independent of PARylation may also participate in maintaining mitochondria homomasis, in light of not all PARPs family members exert its role by PARylation [ 38 , 39 ]. Besides, given that some RNA binding proteins (RBPs) have been identified as essential for adipogenesis and thermoregulation [ 40–42 ], as an RBP, PARP12 may also exert its function by affecting RNA processes and post transcription.…”