PARG inhibition induces nuclear aggregation of PARylated PARP1

• Published in: Structure (London) Vol. 32; no. 11; pp. 2083 - 2093.e5
• Main Authors: Paradkar, Sateja, Purcell, Julia, Cui, Annie, Friedman, Sam, Noronha, Katelyn J., Murray, Matthew A., Sundaram, Ranjini K., Bindra, Ranjit S., Jensen, Ryan B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 07.11.2024
• Subjects: Cell Nucleus - metabolism; DNA Damage; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Glycoside Hydrolases - chemistry; Glycoside Hydrolases - genetics; Glycoside Hydrolases - metabolism; Humans; laser microirradiation; PAR; PARG; PARG inhibitors; PARP1; PARP1 aggregation; Poly (ADP-Ribose) Polymerase-1 - antagonists & inhibitors; Poly (ADP-Ribose) Polymerase-1 - genetics; Poly (ADP-Ribose) Polymerase-1 - metabolism; Poly ADP Ribosylation; Poly(ADP-ribose) Polymerase Inhibitors - pharmacology; Protein Aggregates; PAR; laser microirradiation; PARG; PARP1 aggregation; PARP1; PARG inhibitors
• ISSN: 0969-2126; 1878-4186; 1878-4186
• DOI: 10.1016/j.str.2024.09.006

Poly (ADP-ribose) glycohydrolase (PARG) inhibitors are currently under clinical development for the treatment of DNA repair-deficient cancers; however, their precise mechanism of action is still unclear. Here, we report that PARG inhibition leads to excessive PARylated poly (ADP-ribose) polymerase 1 (PARP1) reducing the ability of PARP1 to properly localize to sites of DNA damage. Strikingly, the mis-localized PARP1 accumulates as aggregates throughout the nucleus. Abrogation of the catalytic activity of PARP1 prevents aggregate formation, indicating that PAR chains play a key role in this process. Finally, we find that PARP1 nuclear aggregates were highly persistent and were associated with cleaved cytoplasmic PARP1, ultimately leading to cell death. Overall, our data uncover an unexpected mechanism of PARG inhibitor cytotoxicity, which will shed light on the use of these drugs as anti-cancer therapeutics. [Display omitted] •PARG inhibition causes nuclear PARP1 aggregation in response to DNA damage•PARP1 aggregates cause the mis-localization of PARP1 away from damage sites•PARP1 aggregates are formed through PAR chains•PARP1 aggregates are associated with cell death Paradkar et al. report that PARG inhibitors induce the formation of nuclear and highly persistent PARP1 aggregates in response to DNA damage. These aggregates require PAR chain synthesis for their formation and cause the mis-localization of PARP1 away from sites of DNA damage, leading to cytotoxicity across cancer cell lines.