Review of Poly (ADP-ribose) Polymerase (PARP) Mechanisms of Action and Rationale for Targeting in Cancer and Other Diseases

Abstract

Poly (ADP-ribose) polymerases (PARPs) are a family of related enzymes that share the ability to catalyze the transfer of ADP-ribose to target proteins. PARPs play an important role in various cellular processes, including modulation of chromatin structure, transcription, replication, recombination, and DNA repair. The role of PARP proteins in DNA repair is of particular interest, in view of the finding that certain tumors defective in homologous recombination mechanisms, may rely on PARP-mediated DNA repair for survival, and are sensitive to its inhibition. PARP inhibitors may also increase tumor sensitivity to DNA-damaging agents. Clinical trials of PARP inhibitors are investigating the utility of these approaches in cancer. The hyperactivation of PARP has also been shown to result in a specific programmed cell death pathway involving NAD+/ATP depletion, mu-calpain activation, loss of mitochondrial membrane potential, and the release of apoptosis inducing factor. Hyperactivation of the PARP pathway may be exploited to selectively kill cancer cells. Other PARP forms, including tankyrase 1 (PARP 5a), which plays an important role in enhancing telomere elongation by telomerase, have been found to be potential targets in cancer therapy. The PARP pathway and its inhibition thus offers a number of opportunities for therapeutic intervention in both cancer and other disease states.

Restoration of TET2 Function Blocks Aberrant Self-Renewal and Leukemia Progression

“…Poly ADP ribose polymerase (PARP) is an essential mediator of BER that targets single-strand breaks (SSBs) induced by DNA damage and recruits BER complex proteins (Morales et al, 2014). The peak of DNA demethylation upon 10 days of Tet2 restoration to cKit + cells correlated with increased expression of Parp and Gadd45 (Figure 7D), whose gene products function in DNA demethylation (Barreto et al, 2007; Ciccarone et al, 2012).…”

Mechanistic Dissection of PARP1 Trapping and the Impact on In Vivo Tolerability and Efficacy of PARP Inhibitors

“…Extensive research has revealed numerous PARP1 functions spanning a diverse array of nuclear processes, including DNA damage repair (2)(3)(4)(5), chromatin remodeling (6), transcriptional regulation (6), telomere maintenance (7), and cell death (8). Owing primarily to the role of PARP1 (and the related but less abundant PARP2 and PARP3) in DNA damage repair, a number of PARP inhibitors are undergoing clinical development as anticancer agents with a focus on tumors with impaired homologous recombination (HR) capability and on combination regimens with DNA-damaging chemotherapy or radiation (9).…”

Targeting Tumour Hypoxia with PARP Inhibitors: Contextual Synthetic Lethality

“…Again, colony survival assays confirmed this hypothesis although it should be noted that the effect was less significant than observed at the lower oxygen level. This is perhaps not surprising given the role of PARP in the response to replication stress [79]. However, our data demonstrating that proliferating hypoxic cells are sensitive to PARP inhibition are extremely promising clinically, as these cells are more abundant and more accessible in a solid tumour.…”