Abstract
Poly(ADP-ribose) polymerases (PARPs) are DNA-dependent nuclear enzymes that transfer negatively charged ADP-ribose moieties from cellular nicotinamide-adenine-dinucleotide (NAD+) to a variety of protein substrates, altering protein–protein and protein-DNA interactions. The most studied of these enzymes is poly(ADP-ribose) polymerase-1 (PARP-1), which is an excellent therapeutic target in cancer due to its pivotal role in the DNA damage response. Clinical studies have shown susceptibility to PARP inhibitors in DNA repair defective cancers with only mild adverse side effects. Interestingly, additional studies are emerging which demonstrate a role for this therapy in DNA repair proficient tumors through a variety of mechanisms. In this review, we will discuss additional functions of PARP-1 – including regulation of inflammatory mediators, cellular energetics and death pathways, gene transcription, sex hormone- and ERK-mediated signaling, and mitosis – and the role these PARP-1-mediated processes play in oncogenesis, cancer progression, and the development of therapeutic resistance. As PARP-1 can act in both a pro- and anti-tumor manner depending on the context, it is important to consider the global effects of this protein in determining when, and how, to best use PARP inhibitors in anticancer therapy.
Highlights
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme which binds DNA via two zinc finger motifs and transfers chains of ADP-ribosyl moieties (PARs) from nicotinamide-adeninedinucleotide (NAD+) to chromatin-associated acceptor proteins, including Poly(ADP-ribose) polymerases (PARPs)-1 itself
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme which binds DNA via two zinc finger motifs and transfers chains of ADP-ribosyl moieties (PARs) from nicotinamide-adeninedinucleotide (NAD+) to chromatin-associated acceptor proteins, including PARP-1 itself. This post-translational modification plays an important role in promoting DNA repair by releasing PARP1 from DNA and allowing for recruitment of proteins involved in both base excisional repair (BER) and homologous recombination (HR) [1]
Perhaps the most well-known tumoricidal effects of PARP inhibitors are in BRCA-mutated cancers, which harbor DNA repair defects and become dependent on PARP-1-mediated repair for survival
Summary
Poly(ADP-ribose) polymerase-1 (PARP-1) is a nuclear enzyme which binds DNA via two zinc finger motifs and transfers chains of ADP-ribosyl moieties (PARs) from nicotinamide-adeninedinucleotide (NAD+) to chromatin-associated acceptor proteins, including PARP-1 itself. Pre-clinical studies have identified susceptibility to PARP inhibition alone in HR-proficient HER2positive breast cancer, pancreatic cancer, prostate cancer, Ewing’s sarcoma, small cell lung carcinoma, and neuroblastoma, among others [12,13,14,15,16,17]. These reports demonstrate the existence of nonDNA repair functions of PARP-1 that may be targetable for cancer treatment.
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