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. 2013 Nov 14;3:279. doi: 10.3389/fonc.2013.00279

Figure 1.

Figure 1

Different mechanisms for therapeutic efficacy of PARPi in cancers. (A) BER/HRR model: this model focuses on the role of PARP-1, the principal target of PARPi, in BER that removes abasic sites and SSB created constantly in the mammalian genome by endogenous oxidants (steps 1A). During BER, the binding of PARP-1 to SSB leads to stimulation of its catalytic activity of forming polymers of ADP-ribose (PAR) from its substrate NAD+. The PAR and PARP-1 interact with and recruit the key BER scaffold protein XRCC1, whereas PAR-modified PARP-1 loses its affinity to bind to SSB and vacates the site for BER to continue. When PARPi suppress the role of PARP-1 in BER (step 2), the unrepaired SSB would accumulate and collapse the DNA replication fork to form potentially lethal DSB (step 3). The normal cells would survive by repairing these DSB by HRR (step 4), but the HRR-deficient BRCA-mutants would die due to unrepaired DSB (step 5) or possibly due to excessive reliance on the error-prone NHEJ repair pathway to remove DSB (step 6). This BER/HRR nexus also explains the effectiveness of combination therapy of PARPi with drugs that cause DNA damage that is repaired by BER (step 1B). Since PARP-2 is also known to play a role in BER, and since current PARPi are also known to inhibit PARP-2, the effect of PARPi may also be mediated by targeting of the functions of PARP-2 in BER, as shown on the target board along with PARP-1. In addition, the inhibitory effect of PARPi on other PARPs could also influence therapeutic efficacy of PARPi (see target board), although their contribution to BER/HRR mediated therapeutic effect of PARPi is not yet fully assessed. (B) Other targets of PARPi that can confer therapeutic benefits of PARPi: PARPi could also be effective anticancer agents by targeting the role of PARP-1 in other DNA repair pathways, such as NER; or other cellular pathways, such as control over cell cycle, tumor angiogenesis, transcription, epithelial-mesenchymal transition (EMT), stress survival response, vasodilation, or tumor-promoting secretome.