Poly ADP Ribose Polymerase - PARP Inactivation

PARP Inactivation

PARP is inactivated by caspase cleavage. It is believed that normal inactivation occurs in systems where DNA damage is extensive. In these cases, more energy would be invested in repairing damage than is feasible, so that energy is instead retrieved for other cells in the tissue through programmed cell death. Besides degradation, there is recent evidence about reversible downregulation mechanisms for PARP, among these an "autoregulatory loop", which is driven by PARP1 itself and modulated by the YY1 transcription factor.

While in vitro cleavage by caspase occurs throughout the caspase family, preliminary data suggest that caspase-3 and caspase-7 are responsible for in vivo cleavage. Cleavage occurs at aspartic acid 214 and glycine 215, separating PARP into a 24kDA and 89kDA segment. The smaller moiety includes the zinc finger motif requisite in DNA binding. The 89 kDa fragment includes the auto-modification domain and catalytic domain. The putative mechanism of PCD activation via PARP inactivation relies on the separation of the DNA-binding region and the auto-modification domain. The DNA-binding region is capable of doing so independent of the rest of the protein, cleaved or not. It is unable, however, to dissociate without the auto-modification domain. In this way, the DNA-binding domain will attach to a damaged site and be unable to effect repair, as it no longer has the catalytic domain. The DNA-binding domain prevents other, non-cleaved PARP from accessing the damaged site and initiating repairs. This model suggests that this “sugar plug” can also begin the signal for apoptosis.