The role of dePARylation in DNA damage repair and cancer suppression

Abstract

Poly(ADP-ribosyl)ation (PARylation) is a reversible post-translational modification regulating various biological pathways including DNA damage repair (DDR). Rapid turnover of PARylation is critically important for an optimal DNA damage response and maintaining genomic stability. Recent studies show that PARylation is tightly regulated by a group of enzymes that can erase the ADP-ribose (ADPR) groups from target proteins. The aim of this review is to present a comprehensive understanding of dePARylation enzymes, their substrates and roles in DDR. Special attention will be laid on the role of these proteins in the development of cancer and their feasibility in anticancer therapeutics.

Figure 1.

Schematic diagram showing that DNA damage-induced PARylation and dePARylation are sequential steps to mediate the recruitment of DDR response proteins. Both single-stranded (SSB) and double-stranded (DSB) breaks on the target DNA are shown. All the poly(ADP-ribose) polymerases (PARPs) are represented as a single color bubble along with the attached PAR chains. Branched, linear PAR chains and mono-ADPR moieties attached to the PARPs are shown. The DNA damage response (DDR) proteins are recruited to the vicinity of the DNA breaks by the ADP-ribosylation. The ADP-ribosylation signals are removed by dePARylation/deMARylation enzymes as shown leading to the recruitment of DDR proteins to the actual damaged site.

Figure 2.

Schematic diagram depicting dePARylation and deMARylationon on a target protein. Ester bond, glycosidic bond, proximal and distal ribose in an ADPR are depicted in the top panel. The enzymes involved in the degradation of the modifications are shown with different color arrows. The arrows point to the bonds digested by the corresponding enzyme. The acceptor protein is shown along with an embedded peptide chain containing different amino acids as beads with their names as depicted. PAR polymer chain with a branch site and MAR sites on the target protein are also depicted. The damaged DNA is depicted on top of the substrate.