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Polymerase independent repression of FoxO1 transcription by sequence-specific PARP1 binding to FoxO1 promoter

文献类型：期刊论文

作者Tian, Yu-Nan1,2; Chen, Hua-Dong1,2; Tian, Chang-Qing1,2; Wang, Ying-Qing1,2; Miao, Ze-Hong1,2,3
刊名CELL DEATH & DISEASE
出版日期2020-01-28
卷号11期号:1页码:12
ISSN号2041-4889
DOI10.1038/s41419-020-2265-y
通讯作者Wang, Ying-Qing(yqwang@simm.ac.cn) ; Miao, Ze-Hong(zhmiao@simm.ac.cn)
英文摘要Poly(ADP-ribose) polymerase 1 (PARP1) regulates gene transcription in addition to functioning as a DNA repair factor. Forkhead box O1 (FoxO1) is a transcription factor involved in extensive biological processes. Here, we report that PARP1 binds to two separate motifs on the FoxO1 promoter and represses its transcription in a polymerase-independent manner. Using PARP1-knock out (KO) cells, wild-type-PARP1-complemented cells and catalytic mutant PARP1(E988K)-reconstituted cells, we investigated transcriptional regulation by PARP1. PARP1 loss led to reduced DNA damage response and similar to 362-fold resistance to five PARP inhibitors (PARPis) in Ewing sarcoma cells. RNA sequencing showed 492 differentially expressed genes in a PARP1-KO subline, in which the FoxO1 mRNA levels increased up to more than five times. The change in the FoxO1 expression was confirmed at both mRNA and protein levels in different PARP1-KO and complemented cells. Moreover, exogenous PARP1 overexpression reduced the endogenous FoxO1 protein in RD-ES cells. Competitive EMSA and ChIP assays revealed that PARP1 specifically bound to the FoxO1 promoter. DNase I footprinting, mutation analyses, and DNA pulldown FREP assays showed that PARP1 bound to two particular nucleotide sequences separately located at -813 to -826 bp and -1805 to -1828 bp regions on the FoxO1 promoter. Either the PARPi olaparib or the PARP1 catalytic mutation (E988K) did not impair the repression of PARP1 on the FoxO1 expression. Exogenous FoxO1 overexpression did not impair cellular PARPi sensitivity. These findings demonstrate a new PARP1-gene promoter binding mode and a new transcriptional FoxO1 gene repressor.
WOS关键词POLY(ADP-RIBOSE) POLYMERASE ; ANTICANCER ACTIVITY ; GENE-EXPRESSION ; CELL VIABILITY ; INHIBITORS ; GROWTH ; OPPORTUNITIES ; RESISTANCE ; MECHANISM ; DISCOVERY
资助项目National Natural Science Foundation of China[81573450] ; National Natural Science Foundation of China[81773764] ; Chinese Academy of Sciences[XDA12020104] ; Chinese Academy of Sciences[XDA12020109] ; Chinese Academy of Sciences[CASIMM0120185003] ; Nova Development Program of the Shanghai Institute of Materia Medica ; Science and Technology Commission of Shanghai Municipality[19ZR1467900] ; State Key Laboratory of Drug Research ; Open Studio for Drugability Research of Marine Natural Products in the Qingdao National Laboratory for Marine Science and Technology
WOS研究方向Cell Biology
语种英语
WOS记录号WOS:000543781300001
出版者NATURE PUBLISHING GROUP
源URL[http://119.78.100.183/handle/2S10ELR8/291766]  
专题新药研究国家重点实验室
通讯作者Wang, Ying-Qing; 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, 19A Yuquan Rd, Beijing 100049, Peoples R China
3.Pilot Natl Lab Marine Sci & Technol, Open Studio Druggabil Res Marine Nat Prod, Qingdao 266237, Shandong, Peoples R China
推荐引用方式
GB/T 7714		 Tian, Yu-Nan,Chen, Hua-Dong,Tian, Chang-Qing,et al. Polymerase independent repression of FoxO1 transcription by sequence-specific PARP1 binding to FoxO1 promoter[J]. CELL DEATH & DISEASE,2020,11(1):12.
APA Tian, Yu-Nan,Chen, Hua-Dong,Tian, Chang-Qing,Wang, Ying-Qing,&Miao, Ze-Hong.(2020).Polymerase independent repression of FoxO1 transcription by sequence-specific PARP1 binding to FoxO1 promoter.CELL DEATH & DISEASE,11(1),12.
MLA Tian, Yu-Nan,et al."Polymerase independent repression of FoxO1 transcription by sequence-specific PARP1 binding to FoxO1 promoter".CELL DEATH & DISEASE 11.1(2020):12.

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来源：上海药物研究所

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