PARP Inhibitors Target the DDR
The biological targets of PARP inhibitors are the PARP enzymes, primarily PARP1 and PARP2. The main function of PARP1 and PARP2 is detection of single-stranded DNA lesions or DNA base damages and signaling to the single strand break repair and base excision repair machinery (Figure 4). This involves attaching poly-ADP-ribose (PAR) moieties to histones and other proteins, including itself, at the site of damage, which stimulates the repair. Inhibiting this enzymatic activity of PARP1 results in decreased PARylation of target molecules including the enzyme itself. As auto-PARylation is needed to remove the PARP enzyme from the site of the lesion, clinical PARP inhibitors in this way also trap the enzyme on the DNA. This results in many unrepaired DNA lesions causing replication associated DSBs, which require repair by HR (Figure 4). As BRCA1 and BRCA2 gene products are important players in HR, this pathway is defective in tumors harboring BRCA1/2 defects. This results in accumulation of toxic DNA damages and cell death upon PARP inhibition. This explains the approximately 1000-fold PARP inhibitor sensitivity in BRCA1/2 defective cells (Figure 4).[20,21]
Inhibiting poly-(ADP-ribose) polymerase is synthetically lethal with homologous recombination deficiency. The PARP enzyme supports single strand break and/or base excision repair and thus prevents stalling/collapsing of replication forks in this way. Inhibiting PARP causes replication forks to collapse and DSBs to be induced. This requires HR for efficient repair. In the case of HR deficiency, for example, BRCA2 defect, this repair will not take place resulting in accumulation of toxic DNA lesions and cell death.
BER: Base excision repair; DSB: Double strand break; HR: Homologous recombination; SSB: Single stranded break.
Personalized Medicine. 2015;12(2):139-154. © 2015 Future Medicine Ltd.