New PARP targets for cancer therapy

Abstract

Poly(ADP-ribose) polymerases (PARPs) modify target proteins post-translationally with poly(ADP-ribose) (PAR) or mono(ADP-ribose) (MAR) using NAD(+) as substrate. The best-studied PARPs generate PAR modifications and include PARP1 and the tankyrase PARP5A, both of which are targets for cancer therapy with inhibitors in either clinical trials or preclinical development. There are 15 additional PARPs, most of which modify proteins with MAR, and their biology is less well understood. Recent data identify potentially cancer-relevant functions for these PARPs, which indicates that we need to understand more about these PARPs to effectively target them.

Figure 1. Sequence and Structural Elements of the PARP catalytic domain

The Donor (yellow) and acceptor (orange) loops of PARP1 (3L3M), which shape the substrate and acceptor binding pockets respectively, are indicated. H-Y-E motif is shown in magenta. A co-crystallized NAD⁺ analog inhibitor (A927929) is shown in cyan.

Figure 2. Two forms of ADPr modifications

PARPs synthesize either mono(ADP-ribose) (MAR) or poly(ADP-ribose) (PAR) modifications. Both can alter target protein function through covalent modification. PAR can also function as a scaffold to recruit proteins containing macro, WWE, PBZ and PBM domains. In contrast, MAR is only recognized by macro domains and does not act as a scaffold since it only contains a single binding site for proteins. Therefore, the structural distinction between MAR and PAR has important consequences of the mechanism of function of the modification.

Figure 3. Cellular Functions of the PARP Family

PARPs have multiple diverse in functions in physiological pathways including cell migration, transcriptional regulation, signal transduction, miRNA-mediated gene silencing, regulation of membrane organelles and telomere length regulation. Additionally, PARPs function in stress-responsive cellular pathways upon DNA damage, cytoplasmic stress, environmental stress and ER stress, activating DNA damage repair, stress granule assembly, the heat shock response and the ER unfolded protein response pathways in response. Many of these physiological and stress response pathways are misregulated in cancer, raising the possibility that inhibition of these PARP functions could have therapeutic benefits.