The dynamic process of covalent and non-covalent PARylation in the maintenance of genome integrity: a focus on PARP inhibitors

Abstract

Poly(ADP-ribosylation) (PARylation) by poly(ADP-ribose) polymerases (PARPs) is a highly regulated process that consists of the covalent addition of polymers of ADP-ribose (PAR) through post-translational modifications of substrate proteins or non-covalent interactions with PAR via PAR binding domains and motifs, thereby reprogramming their functions. This modification is particularly known for its central role in the maintenance of genomic stability. However, how genomic integrity is controlled by an intricate interplay of covalent PARylation and non-covalent PAR binding remains largely unknown. Of importance, PARylation has caught recent attention for providing a mechanistic basis of synthetic lethality involving PARP inhibitors (PARPi), most notably in homologous recombination (HR)-deficient breast and ovarian tumors. The molecular mechanisms responsible for the anti-cancer effect of PARPi are thought to implicate both catalytic inhibition and trapping of PARP enzymes on DNA. However, the relative contribution of each on tumor-specific cytotoxicity is still unclear. It is paramount to understand these PAR-dependent mechanisms, given that resistance to PARPi is a challenge in the clinic. Deciphering the complex interplay between covalent PARylation and non-covalent PAR binding and defining how PARP trapping and non-trapping events contribute to PARPi anti-tumour activity is essential for developing improved therapeutic strategies. With this perspective, we review the current understanding of PARylation biology in the context of the DNA damage response (DDR) and the mechanisms underlying PARPi activity and resistance.

Poly (ADP-ribose): A double-edged sword governing cancer cell survival and death

“…This biochemical action yields a linear or branched conformation, depending on whether the ADP-ribose is attached to the 2’-OH terminus of a growing chain or an ADP-ribose residue adjacent to the PARylation target[ 2 , 3 ]. The formation of PAR enables it to interact non-covalently with other molecules and act as a regulator mediating physiological signals involving potential molecular biological and biochemical reactions[ 4 ]. Recent studies have shown that PAR could a significant role in the entire process of carcinogenesis, including initiation, promotion, progression, and metastasis[ 5 ].…”

Editorial: DNA repair and nucleic acid therapeutics in cancer

“…( 43 ), and the mechanism of PARylation, both covalent and non-covalent, is summarized by Beneyton et al. ( 44 ). Further, Dhoonmoon et al.…”