An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Kruppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress
文献类型：期刊论文
| 作者 | Kuo, Ching-Ying1,2; Li, Xu1; Kong, Xiang-Qian3; Luo, Cheng3 ; Chang, Che-Chang4; Chung, Yiyin1; Shih, Hsiu-Ming4; Li, Keqin Kathy5; Ann, David K.1,2
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| 刊名 | JOURNAL OF BIOLOGICAL CHEMISTRY
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| 出版日期 | 2014-07-25 |
| 卷号 | 289期号:30页码:20757-20772 |
| ISSN号 | 0021-9258 |
| DOI | 10.1074/jbc.M114.555672 |
| 文献子类 | Article |
| 英文摘要 | Kruppel-associated box domain-associated protein 1 (KAP1) is a universal transcriptional corepressor that undergoes multiple posttranslational modifications (PTMs), including SUMOylation and Ser-824 phosphorylation. However, the functional interplay of KAP1 PTMs in regulating KAP1 turnover during DNA damage response remains unclear. To decipher the role and cross-talk of multiple KAP1 PTMs, we show here that DNA double strand break-induced KAP1 Ser-824 phosphorylation promoted the recruitment of small ubiquitin-like modifier (SUMO)-targeted ubiquitin E3 ligase, ring finger protein 4 (RNF4), and subsequent RNF4-mediated, SUMO-dependent degradation. Besides the SUMO interacting motif (SIM), a previously unrecognized, but evolutionarily conserved, arginine-rich motif (ARM) in RNF4 acts as a novel recognition motif for selective target recruitment. Results from combined mutagenesis and computational modeling studies suggest that RNF4 utilizes concerted bimodular recognition, namely SIM for Lys-676 SUMOylation and ARM for Ser(P)-824 of simultaneously phosphorylated and SUMOylated KAP1 (Ser(P)-824-SUMO-KAP1). Furthermore, we proved that arginines 73 and 74 within the ARM of RNF4 are required for efficient recruitment to KAP1 or accelerated degradation of promyelocytic leukemia protein (PML) under stress. In parallel, results of bimolecular fluorescence complementation assays validated the role of the ARM in recognizing Ser(P)-824 in living cells. Taken together, we establish that the ARM is required for RNF4 to efficiently target Ser(P)-824-SUMO-KAP1, conferring ubiquitin Lys-48-mediated proteasomal degradation in the context of double strand breaks. The conservation of such a motif may possibly explain the requirement for timely substrate selectivity determination among a myriad of SUMOylated proteins under stress conditions. Thus, the ARM dynamically regulates the SIM-dependent recruitment of targets to RNF4, which could be critical to dynamically fine-tune the abundance of Ser(P)-824-SUMO-KAP1 and, potentially, other SUMOylated proteins during DNA damage response. |
| WOS关键词 | DNA-DAMAGE RESPONSE ; DOUBLE-STRAND BREAKS ; BIMOLECULAR FLUORESCENCE COMPLEMENTATION ; UBIQUITIN E3 LIGASE ; PML NUCLEAR-BODIES ; ZINC-FINGER ; POSTTRANSLATIONAL MODIFICATIONS ; FAMILY PROTEINS ; SUMO ; REPAIR |
| 资助项目 | National Institute of Health[R01DE10742] ; National Institute of Health[R01DE14183] ; National Science Council[99-2321-B-001-010] ; National Science Council[98-2321-B-001-012] ; National 973 Program[2011CB510102] ; National Natural Science Foundation[81270622] |
| WOS研究方向 | Biochemistry & Molecular Biology |
| 语种 | 英语 |
| WOS记录号 | WOS:000339396600032 |
| 出版者 | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/276977]  |
| 专题 | 药物发现与设计中心 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Li, Keqin Kathy |
| 作者单位 | 1.City Hope Natl Med Ctr, Beckman Res Inst, Dept Mol Pharmacol, Duarte, CA 91010 USA; 2.City Hope Natl Med Ctr, Beckman Res Inst, Irell & Manella Grad Sch Biol Sci, Duarte, CA 91010 USA; 3.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 4.Acad Sinica, Inst Biomed Sci, Taipei 11529, Taiwan; 5.Shanghai Jiao Tong Univ, Sch Med, State Key Lab Med Genom, Shanghai Inst Hematol,Rui Jin Hosp, Shanghai 200025, Peoples R China |
| 推荐引用方式 GB/T 7714 | Kuo, Ching-Ying,Li, Xu,Kong, Xiang-Qian,et al. An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Kruppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2014,289(30):20757-20772. |
| APA | Kuo, Ching-Ying.,Li, Xu.,Kong, Xiang-Qian.,Luo, Cheng.,Chang, Che-Chang.,...&Ann, David K..(2014).An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Kruppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress.JOURNAL OF BIOLOGICAL CHEMISTRY,289(30),20757-20772. |
| MLA | Kuo, Ching-Ying,et al."An Arginine-rich Motif of Ring Finger Protein 4 (RNF4) Oversees the Recruitment and Degradation of the Phosphorylated and SUMOylated Kruppel-associated Box Domain-associated Protein 1 (KAP1)/TRIM28 Protein during Genotoxic Stress".JOURNAL OF BIOLOGICAL CHEMISTRY 289.30(2014):20757-20772. |
入库方式： OAI收割
来源：上海药物研究所
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