Poly PARP hypothesis

The poly(ADP-ribose) polymerase (PARP) hypothesis in which DNA strand breaks, induced by mustard, activates the nuclear enzyme PARP culminating in metabohc dismp-tion and protease activation in the region of the basal epidermal cells (Papirmeister et al., 1985). 

The second hypothesis addresses the possibility that the premamre formation of the Dnmtl complex, occurrii in cells where PARP activity was previously inhibited, is based on a role of poly(ADP-ribosyl)ation as an ep enetic modification involved in inhibitii Dnmtl-PCNA complex formation and facilitatii complex formation with p21. The fact that PARP inhibition induces hyperexpression of Dnmtl does not allow one to decide whether poly(ADP-ribosyl)ation plays a role in modulatii the affinity of p21 and Dnmtl for PCNA. Pe cannot exclude this second hypothesis, since from literature it is dear that PCNA exists in a poly(ADP-ribosyl)ated isoform in cells and althoi it has been shown recendy that the association between p21 and PCNA is not influenced by the presence of ADP-ribose polymers, the possibility that poly(ADP-ribosyl)ation is involved in modulatii the association between Dnmtl and PCNA cannot be excluded. It could be that both mechanisms are involved synei tically. 

The mechanism underlying the potentiation ofTopo I poisons by PARP inhibitors has not been fully elucidated, but could be a function ofTopo I activity or DNA repair. PARP-1 poly(ADP-ribosylates) Topo I, down-r ulating its activity in vitro and in intact cells and inhibition of PARP may therefore increase Topo I activity and hence sensitivity to Topo I poisons. Mattern et al su sted that sensitisation to camptothecin they observed with 3AB was due to de-repression of topoisomerase activity rather than a direct effect of PARP inhibition on DNA repair. " Consistent with this hypothesis is the observation that Topo I was activated 800% association with PARP-1 but poly(ADP-ribosylation) ofTopo I or its association with automodified PARP-1 inhibited Topo I activity, which could be restored in the presence of 1 mM benzamide. These studies demonstrated that association with unmodified PARP enhanced Topo I DNA binding and strand scission, but that poly(ADP-ribosylated) PARP probably repels Topo I from the DNA. 

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