Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity
文献类型：期刊论文
| 作者 | Chen, Hua-Dong1,2; Chen, Chuan-Huizi1,2; Wang, Yu-Ting1,2; Guo, Ne1,2; Tian, Yu-Nan1,2; Huan, Xia-Juan1,2; Song, Shan-Shan1,2; He, Jin-Xue1,2; Miao, Ze-Hong1,2,3 |
| 刊名 | INTERNATIONAL JOURNAL OF CANCER
 |
| 出版日期 | 2019-08-01 |
| 卷号 | 145期号:3页码:714-727 |
| 关键词 | PARP1 inhibitor PARP1-DNA binding PARP1-DNA trapping poly(ADP-ribose) polymerase activity cytotoxicity |
| ISSN号 | 0020-7136 |
| DOI | 10.1002/ijc.32131 |
| 文献子类 | Article |
| 英文摘要 | PARP1 inhibitors (PARPis) are used clinically during cancer therapy and are thought to exert their cytotoxicity through PARP1 polymerase inhibition and PARP1-DNA trapping. Here, we showed no significant correlation between PARP1-DNA trapping and cytotoxicity induced by PARPis. We complemented PARP1-knockout sublines with wild-type PARP1 and 11 mutants with different point mutations that affect the polymerase activity. When examining the PARPi talazoparib, the induced cytotoxicity was highly significantly correlated with cellular PARP1 polymerase activity, but not with its PARP1-DNA trapping or polymerase inhibition. Similarly, talazoparib's PARP1-DNA trapping revealed significant correlation with the polymerase activity rather than its inhibition. Differently, however, when evaluating purified wild-type and mutated PARP1, we identified an almost linear relationship between PARPis' inhibiting PARP1 dissociation from DNA and their cytotoxicity in 17 cancer cell lines. In contrast, no significant correlation existed between PARP1 polymerase inhibition in the histone-based systems and the cytotoxicity. After careful comparisons on different methods and detection targets, we conclude that the PARPi-mediated increase in PARP1-DNA binding by inhibiting autoPARylation of PARP1 on DNA rather than in PARP1-DNA trapping is correlated with PARPi's cytotoxicity. Accordingly, we established a new PARPi screening model that more closely predicts cytotoxicity. |
| WOS关键词 | POLY(ADP-RIBOSE) POLYMERASE ; ANTICANCER ACTIVITY ; STRUCTURAL BASIS ; HIGHLY POTENT ; BMN 673 ; DISCOVERY ; DESIGN ; OPPORTUNITIES ; MECHANISM ; EFFICACY |
| WOS研究方向 | Oncology |
| 语种 | 英语 |
| WOS记录号 | WOS:000470911700015 |
| 出版者 | WILEY |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/309424]  |
| 专题 | 新药研究国家重点实验室 |
| 通讯作者 | Miao, Ze-Hong |
| 作者单位 | 1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Univ Chinese Acad Sci, Beijing, Peoples R China; 3.Pilot Natl Lab Marine Sci & Technol Qingdao, Open Studio Druggabil Res Marine Nat Prod, Qingdao, Shandong, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chen, Hua-Dong,Chen, Chuan-Huizi,Wang, Yu-Ting,et al. Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity[J]. INTERNATIONAL JOURNAL OF CANCER,2019,145(3):714-727. |
| APA | Chen, Hua-Dong.,Chen, Chuan-Huizi.,Wang, Yu-Ting.,Guo, Ne.,Tian, Yu-Nan.,...&Miao, Ze-Hong.(2019).Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity.INTERNATIONAL JOURNAL OF CANCER,145(3),714-727. |
| MLA | Chen, Hua-Dong,et al."Increased PARP1-DNA binding due to autoPARylation inhibition of PARP1 on DNA rather than PARP1-DNA trapping is correlated with PARP1 inhibitor's cytotoxicity".INTERNATIONAL JOURNAL OF CANCER 145.3(2019):714-727. |
入库方式： OAI收割
来源：上海药物研究所
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