Beyond DNA Repair: Additional Functions of PARP-1 in Cancer

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.

Keywords: ERK signaling; NF-κB; PARP inhibitors; PARP-1; angiogenesis; genetic transcription; mitotic spindle; sex hormone signaling.

Figure 1

Non-DNA repair functions of PARP-1 influence the “hallmarks of cancer” (18). This schematic depicts multiple PARP-1-mediated processes which either stimulate or inhibit six of the eight “hallmarks of cancer,” as indicated by green and red boxes respectively. These hallmarks, proposed by Hanahan and Weinberg, are malignant characteristics that provide a framework for understanding the biology of cancer.

Figure 2

Poly(ADP-ribose) polymerase-1 mediates activation of NF-κB signaling. (Left) inflammatory stimulation triggers p300/CBP acetylation of PARP-1, enhancing the interaction between p50 and PARP-1 as well as the p50–p300 interaction; this ultimately leads to activation of NF-κB. (Right) DNA damage detection promotes the formation of a complex including PARP-1, ATM, PIASγ, and IKKγ (NEMO); chains of PAR on PARP-1 provide a structure upon which PIASγ SUMOylates IKKγ, leading to NF-κB activation.

Figure 3

Poly(ADP-ribose) polymerase-1 acts as a switch between cell fates. Hyperactivation of PARP-1 and PAR synthesis depletes NAD and, subsequently, ATP. Elevated PAR can promote necrosis, autophagy, or AIF-induced parthanatos. In addition, PARylation inactivates caspase-8, inhibiting apoptotic signaling. Alternatively, activated caspases can cleave PARP-1; the resulting cleavage product inhibits uncleaved PARP-1, conserving NAD/ATP, and promoting apoptosis. These cell death pathways play a role in both cancer survival and response to anticancer therapy.

Figure 4

Poly(ADP-ribose) polymerase-1-regulates gene transcription through multiple mechanisms. [1] PARP-1 binds neighboring nucleosomes resulting in chromatin compaction. [2] PARP-1 PARylation of core histones mediates chromatin relaxation. [3] PARP-1 promotes hypomethylation of DNA by enhancing the chromatin insulator activity of CCCTC-binding factor (CTCF) while inhibiting methyltransferase activity of DNMT1. [4] PARP-1 promotes loading and retention of RNA polymerase II at active promoters. [5] PARP-1 binds regulatory DNA sequences and transcription factors, PARylates transcription factors, and recruits additional regulatory binding proteins in a target gene specific manner.