The role of PARP in DNA repair and its therapeutic exploitation

Abstract

Historically, PARP inhibitors (PARPi) were developed to potentiate the cytotoxic effect of certain chemotherapeutic agents and are currently being investigated in combination with chemotherapy in diverse cancer types. These agents are also radiosensitisers and clinical trials of PARPi with concurrent radiation are required. It has long been recognised that defective DNA repair pathways lead to tumour susceptibility. Recent studies indicate that tumour cells with defective homologous recombination (HR) repair pathways, the classic example being BRCA mutations, are exquisitely sensitive to PARPi. Defects in HR are not restricted to BRCA-associated tumours and other cancer types may be enriched for HR defects and hence susceptible to PARP inhibition. The identification of predictive markers for sensitivity to PARP inhibition is a priority area for research.

Figure 1

Catalytic activity of PARP-1 and role in DNA BER/SSBR. PARP cleaves NAD⁺ releasing nicotinamide; the ADP-ribose polymers are covalently attached to acceptor proteins, such as PARP itself and histones. These loosen the chromatin and recruit the scaffold protein XRCC1 (X) and other histone remodelling enzymes, which in turn recruits DNA polymerase β (β) and ligase III (3) to fill in and re-seal the gap. The polymers are degraded by poly ADP-ribose glycohydrolase (PARG), releasing unmodified PARP to bind other DNA breaks.

Figure 2

DNA repair and the role of PARP-1/2 in synthetic lethality and chemo- or radiosensitisation. (A) Synthetic lethality: endogenously induced, or cytotoxic agent-induced, DNA SSBs are repaired by PARP-dependent BER/SSBR to promote survival. If repair is incomplete, then in proliferating cells, the SSBs will cause replication fork stalling and replication-associated DSBs. These are preferentially repaired by error-free HR to promote cell survival. HR is a complex process involving a multitude of proteins, including BRCA1 and 2, only a few of which are illustrated here. When HR is defective, DSBs persist or are repaired by error-prone SSA or NHEJ, resulting in cell death. (B) Chemo- and radiosensitisation. Genotoxic agent-induced DNA breaks normally repaired by PARP-dependent pathways accumulate in the presence of a PARPi, overwhelming alternative repair pathways, converting repairable to unrepairable damage. This ultimately results in cell death.