PARylation is a transient posttranslational modification and is quickly degraded by dePARylation enzymes, such as poly(ADP-ribose) glycohydrolase (PARG) . PARG specifically hydrolyzes the glycosidic bonds between ADP-ribose units in PAR chains and is the major dePARylation enzyme that accounts for ~90% of dePARylation activity . Notably, similar to PARPs, PARG also facilitates both DNA double-strand break (DSB) and single-strand break (SSB) repair . Following DNA damage, a number of DNA damage response factors recognize PARylation and are recruited by PARylation to the proximity of DNA lesions . However, PARylation has to be digested so that DNA damage machinery directly recognizes DNA lesions and repairs lesions . Otherwise, the repair machineries will be trapped by PARylation at the vicinity of DNA lesions. Thus, dePARylation is an immediate downstream step of PARylation in DNA repair, and suppression of dePARylation will affect PARylation-dependent DNA repair. It indicates that targeting dePARylation, similar to targeting PARPs, may selectively kill tumor cells with DNA repair defects.

Reference
Pubmed: Chen SH, Yu X. Targeting dePARylation selectively suppresses DNA repair-defective and PARP inhibitor-resistant malignancies. Sci Adv. 2019 Apr 10;5(4):eaav4340. doi: 10.1126/sciadv.aav4340.