Poly(ADP-ribose) polymerases (PARPs) are a family of enzymes that catalyze the addition of poly(ADP-ribose) (PAR) subunits onto themselves and other acceptor proteins. PARPs are known to function in a large range of cellular processes including DNA repair, DNA replication, transcription and modulation of chromatin structure. Inhibition of PARP holds great potential for therapy, especially in cancer. Several PARP1/2/3 inhibitors (PARPi) have had success in treating ovarian, breast and prostate tumors harboring defects in the homologous recombination (HR) DNA repair pathway, especially BRCA1/2 mutated tumors. However, treatment is limited to specific sub-groups of patients and resistance can occur, limiting the use of PARPi. Poly(ADP-ribose) glycohydrolase (PARG) reverses the action of PARP enzymes, hydrolysing the ribose-ribose bonds present in poly(ADP-ribose). Like PARPs, PARG is involved in DNA replication and repair and PARG depleted/inhibited cells show increased sensitivity to DNA damaging agents. They also display an accumulation of perturbed replication intermediates which can lead to synthetic lethality in certain contexts. In addition, PARG is thought to play an important role in preventing the accumulation of cytoplasmic PAR and therefore parthanatos, a caspase-independent PAR-mediated type of cell death. In contrast to PARP, the therapeutic potential of PARG has been largely ignored. However, several recent papers have demonstrated the exciting possibilities that inhibitors of this enzyme may have for cancer treatment, both as single agents and in combination with cytotoxic drugs and radiotherapy. This article discusses what is known about the functions of PARP and PARG and the potential future implications of pharmacological inhibition in anti-cancer therapy.

聚（ADP-核糖）聚合酶（PARP）是一族酶，可催化聚（ADP-核糖）（PAR）亚基加到自身和其他受体蛋白上。已知PARP在许多细胞过程中起作用，包括DNA修复，DNA复制，染色质结构的转录和调节。抑制PARP具有巨大的治疗潜力，尤其是在癌症中。几种PARP1 / 2/3抑制剂（PARPi）已成功治疗卵巢，乳腺和前列腺肿瘤，这些肿瘤在同源重组（HR）DNA修复途径中存在缺陷，尤其是BRCA1 / 2突变的肿瘤。但是，治疗仅限于特定的患者亚组，可能会产生耐药性，从而限制了PARPi的使用。聚（ADP-核糖）糖水解酶（PARG）逆转PARP酶的作用，水解聚（ADP-核糖）中存在的核糖-核糖键。像PARPs一样，PARG参与DNA复制和修复，PARG耗尽/抑制的细胞对DNA损伤剂的敏感性增加。它们还显示出受干扰的复制中间体的积累，在某些情况下可能导致合成杀伤力。此外，PARG被认为在防止细胞质PAR积累以及防止parthanatos积累方面起着重要作用，parthanatos是caspase依赖的PAR介导的细胞死亡类型。与PARP相比，PARG的治疗潜力已被大大忽略。但是，最近的几篇论文证明了这种酶抑制剂作为单一药物以及与细胞毒性药物和放射疗法的结合，可能具有令人兴奋的癌症治疗可能性。