Institute for Cancer Genetics, Vagelos College for Physicians and Surgeons, Columbia University, New York, NY 10032, U.S.A.
Departments of Pediatrics, Pathology and Cell Biology, and Immunology and Microbiology, Vagelos College for Physicians and Surgeons, Columbia University, New York, NY 10032, U.S.A.
Biochem Soc Trans. 2022 Aug 31;50(4):1169-1177. doi: 10.1042/BST20220366.
Poly (ADP-ribose) polymerase-1 (PARP1) and 2 (PARP2) are two DNA damage-induced poly (ADP-ribose) (PAR) polymerases in cells and are the targets of PARP inhibitors used for cancer therapy. Strand breaks recruit and activate PARP1 and 2, which rapidly generate PAR from NAD+. PAR promotes the recruitment of other repair factors, relaxes chromatin, and has a role in DNA repair, transcription regulation, and RNA biology. Four PARP1/2 dual inhibitors are currently used to treat BRCA-deficient breast, ovarian, prostate, and pancreatic cancers. In addition to blocking the enzymatic activity of PARP1 and 2, clinical PARP inhibitors extend the appearance of PARP1 and PARP2 on chromatin after damage, termed trapping. Loss of PARP1 confers resistance to PARP inhibitors, suggesting an essential role of trapping in cancer therapy. Yet, whether the persistent PARP1 and 2 foci at the DNA damage sites are caused by the retention of the same molecules or by the continual exchange of different molecules remains unknown. Here, we discuss recent results from quantitative live-cell imaging studies focusing on PARP1 and PARP2's distinct DNA substrate specificities and modes of recruitment and trapping with implications for cancer therapy and on-target toxicities of PARP inhibitors.
聚（ADP-核糖）聚合酶 1（PARP1）和 2（PARP2）是细胞中两种 DNA 损伤诱导的多聚（ADP-核糖）（PAR）聚合酶，是用于癌症治疗的 PARP 抑制剂的靶标。链断裂招募并激活 PARP1 和 PARP2，它们迅速从 NAD+生成 PAR。PAR 促进其他修复因子的募集，使染色质松弛，并在 DNA 修复、转录调控和 RNA 生物学中发挥作用。目前有四种 PARP1/2 双重抑制剂用于治疗 BRCA 缺陷型乳腺癌、卵巢癌、前列腺癌和胰腺癌。除了阻断 PARP1 和 PARP2 的酶活性外，临床 PARP 抑制剂还会延长损伤后染色质上 PARP1 和 PARP2 的出现，称为捕获。PARP1 的缺失赋予了对 PARP 抑制剂的抗性，表明捕获在癌症治疗中具有重要作用。然而，DNA 损伤部位持续存在的 PARP1 和 PARP2 焦点是由相同分子的保留还是由不同分子的连续交换引起的尚不清楚。在这里，我们讨论了最近来自定量活细胞成像研究的结果，这些研究集中在 PARP1 和 PARP2 的不同 DNA 底物特异性以及募集和捕获的模式上，这些结果对癌症治疗和 PARP 抑制剂的靶毒性具有重要意义。
