Parthanatos, a messenger of death

Abstract

Poly-ADP-ribose polymerase-1 (PARP-1)'s roles in the cell span from maintaining life to inducing death. The processes PARP-1 is involved in include DNA repair, DNA transcription, mitosis, and cell death. Of PARP-1's different cellular functions, its role in cell death is of particular interest to designing therapies for diseases. Genetic deletion of PARP-1 revealed that PARP-1 overactivation underlies cell death in models of stroke, diabetes, inflammation and neurodegeneration. Since interfering with PARP-1 mediated cell death will be clinically beneficial, great effort has been invested into understanding mechanisms downstream of PARP-1 overactivation. Recent evidence shows that poly-ADP ribose (PAR) polymer itself can act as a cell death effector downstream of PARP-1. We coined the term parthanatos after Thanatos, the personification of death in Greek mythology, to refer to PAR-mediated cell death. In this review, we will present evidence and questions raised by these recent findings, and summarize the proposed mechanisms by which PARP-1 overactivation kills. It is evident that further understanding of parthanatos opens up new avenues for therapy in ameliorating diseases related to PARP-1 overactivation.

Figure 1

PARP domain. PARP-1 uses NAD⁺ to form polymers of ADP-ribose on various protein acceptors. The major domains of PARP-1 include: (1) two zinc fingers responsible for PARP-1's detection of DNA breaks, (2) nuclear localization signal (NLS) containing a caspase-cleavage site, (3) an automodification domain with a BRCT motif for protein-protein interactions, (4) a catalytic site which contains the PARP signature NAD+-fold.

Figure 2

PAR polymer metabolism. In the initiation step of PAR synthesis (1), PARP-1 converts NAD⁺ to ADP-ribose and nicotinamide. The ADP-ribose is then attached to a glutamic acid residue in the protein acceptor. Structural heterogeneity of the PAR polymer is achieved by elongation (2) and branching (3) at the 2’-OH and 2”-OH of the ribose moiety respectively. PAR breakdown (4) is catalyzed by the endoglycosidic and exoglycosidic activities of PARG. Removal of the final ADP-ribose in the protein acceptor is catalyzed by mono-ADP-ribosyl-protein lyase.

Figure 3

PARP-1 overactivation leads to cell death. In the presence of death stimuli such as excessive DNA damage (1), PARP-1 overactivation (2) leads to the release of the death effector AIF from the mitochondria (3). The biochemical events mediating this nuclear-mitochondrial crosstalk are not completely known. Excess free or protein-bound complex PAR polymer may move from the nuclei to the cytosol where it disrupts protein-protein interactions. Since loss of mitochondrial membrane potential was observed in PARP-1 mediated cell death, PAR possibly binds cytosolic or mitochondrial proteins with roles in AIF release, mitochondrial membrane permeabilization or mitochondrial function. Other events downstream of PARP-1 overactivation include calpain activation, and Bax translocation to the mitochondria. These events appear to be important for AIF release: calpain is hypothesized to cleave AIF which is then released from mitochondria through pores formed by Bax.