Targeting dePARylation for cancer therapy

Abstract

Poly(ADP-ribosyl)ation (PARylation) mediated by poly ADP-ribose polymerases (PARPs) plays a key role in DNA damage repair. Suppression of PARylation by PARP inhibitors impairs DNA damage repair and induces apoptosis of tumor cells with repair defects. Thus, PARP inhibitors have been approved by the US FDA for various types of cancer treatment. However, recent studies suggest that dePARylation also plays a key role in DNA damage repair. Instead of antagonizing PARylation, dePARylation acts as a downstream step of PARylation in DNA damage repair. Moreover, several types of dePARylation inhibitors have been developed and examined in the preclinical studies for cancer treatment. In this review, we will discuss the recent progress on the role of dePARylation in DNA damage repair and cancer suppression. We expect that targeting dePARylation could be a promising approach for cancer chemotherapy in the future.

Keywords: ADP-ribosylation; Cancer therapy; DNA damage response; PARG; dePARylation.

Fig. 1

Schematic diagram showing the proteins involved in dePARylation. The acceptor protein is shown as beads on a string. The dominant amino acids involved in PARylation (i.e. aspartic acid and glutamic acid are shown light blue, arginine is shown in dark blue, serine is shown in light green). A dsDNA helix is and MAR moiety attached to it is shown in black. The bonds hydrolyzed by different dePARylation proteins are shown. A linear and branched PAR chain is shown attached to aspartic acid and glutamic acid

Fig. 2

Schematic diagram showing the effect of dePARylation inhibitors on DDR. A damaged (star) DNA is shown on the top. PARP proteins (PARP1/2) are recruited to the site where they undergo PARylation and MARylation. The PAR/MAR moieties recruit DDR proteins to the vicinity of the damaged site. DePARylation (i.e. by PARG) digests the PAR chains, relives the PARP proteins and loads the DDR on the damaged site. DePARylation inhibitors trap the DDR on the PAR chains thereby preventing DDR and leading to cell death