Role of PARG in Excitotoxicity and PARMediated Cell Death

Poly(ADP-ribose) glycohydrolase (PARG) is an important cellular enzyme that together with PARPs plays an important role in balancing PAR levels in cells. Many genes encoding different PARPs have been identified, whereas only a single gene encoding for PARG has been identified so far. The full length nuclear PARG in humans is 111 kDa with two cytosolic splice variants, 102 and 99 kDa (Meyer-Ficca et al. 2004). PARG catalyzes the hydrolysis of PAR to ADP-ribose units through its glycosidic activity (Davidovic et al. 2001). Evidence from recent data shows that PARG is critical for cell survival. Genetic deletion of PARG results in accumulation of PAR, which leads to early embryonic lethality in drosophila and mice (Hanai et al. 2004; Koh et al. 2004). Conversely, overexpression of PARG leads to protection against excitotoxicity and PARP-1 dependent cell death (Andrabi et al. 2006; Cozzi et al. 2006).

  1. 5.3 Caspase-dependent vs. caspase-independent neuronal cell death. Caspase-dependent and caspase-independent cell death is signaled by factors released from the mitochondria. In traditional caspase-dependent apoptotic cell death, Bcl family proteins and caspase activation are required for execution of cell death. In caspase-independent cell death, AIF acts as a factor to mediate cell death. Release of AIF from mitochondria can be triggered by different cell signaling mechanisms. In parthanatos, it is PAR polymer generated by over-activation of PARP-1 that induces AIF release. Ongoing questions for investigation are: how PAR travels from the nucleus to the mitochondria, how PAR induces the release of AIF and how nuclear AIF results in DNA fragmentation and nuclear shrinkage
  2. 5.3 Caspase-dependent vs. caspase-independent neuronal cell death. Caspase-dependent and caspase-independent cell death is signaled by factors released from the mitochondria. In traditional caspase-dependent apoptotic cell death, Bcl family proteins and caspase activation are required for execution of cell death. In caspase-independent cell death, AIF acts as a factor to mediate cell death. Release of AIF from mitochondria can be triggered by different cell signaling mechanisms. In parthanatos, it is PAR polymer generated by over-activation of PARP-1 that induces AIF release. Ongoing questions for investigation are: how PAR travels from the nucleus to the mitochondria, how PAR induces the release of AIF and how nuclear AIF results in DNA fragmentation and nuclear shrinkage

Mouse trophoblasts from E3.5 PARG null mice survive only in the presence of the PARP inhibitor benzamide. Withdrawal of the PARP inhibitor results in cell death in the PARG trophoblasts via toxic accumulation of PAR (Koh et al. 2004). Delivery of purified PAR results in parthanatos in cultured cells. PAR-mediated cell death is inhibited by PARG overexpression. Consistent with these findings, pre-digestion of PAR with recombinant PARG results in the inability of PAR to induce cell death (Andrabi et al. 2006). The inactivation of PAR by PARG predigestion, shows that PARG is important for cell survival and that PAR is a death signaling molecule. Although only one gene for PARG has been discovered, recent data show that a 39-kDa ADP-ribose-(arginine) protein hydrolase (ARH3) has PARG-like activity with unknown biological significance (Oka et al. 2006). The role of ARH3 in PARP-1 dependent cell death and exci-totoxicity is still to be characterized. The cell survival role of ARH3 seems to be less important based on the lack of compensation in PARG null mice and drosophila.

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