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The methyltransferase PRMT1 regulates γ-globin translation

文献类型：期刊论文

作者Wang, Ying1,2,3; Li, Xinyu1; Ge, Jingru1; Liu, Ming1; Pang, Xiaming2,3; Liu, Jianpeng1; Luo, Cheng4; Xu, Yichen2,3,5; Zhao, Quan1
刊名JOURNAL OF BIOLOGICAL CHEMISTRY
出版日期2021-03-11
卷号296页码:100417
DOI10.1016/j.jbc.2021.100417
文献子类Article
英文摘要Induction of fetal hemoglobin to overcome adult beta-globin gene deficiency is an effective therapeutic strategy to ameliorate human beta-hemoglobinopathies. Previous work has revealed that fetal gamma-globin can be translationally induced via integrated stress signaling, but other studies have indicated that activating stress may eventually suppress gamma-globin expression transcriptionally. The mechanism by which gamma-globin expression is regulated at the translational level remains largely unknown, limiting our ability to determine whether activating stress is a realistic therapeutic option for these disorders. In this study, we performed a functional CRISPR screen targeting protein arginine methyltransferases (PRMTs) to look for changes in gamma-globin expression in K562 cells. We not only discovered that several specific PRMTs may block gamma-globin transcription, but also revealed PRMT1 as a unique family member that is able to suppress gamma-globin synthesis specifically at the translational level. We further identified that a non-AUG uORF within the 5' untranslated region of gamma-globin serves as a barrier for translation, which is bypassed upon PRMT1 deficiency. Finally, we found that this novel mechanism of gamma-globin suppression could be pharmacologically targeted by the PRMT1 inhibitor, furamidine dihydrochloride. These data raise new questions regarding methyltransferase function and may offer a new therapeutic direction for beta-hemoglobinopathies.
WOS关键词FETAL-HEMOGLOBIN ; GENE-EXPRESSION ; BETA-THALASSEMIA ; INITIATION ; METHYLATION ; INDUCTION ; REVEALS ; RECOGNITION ; EFFICIENCY ; INHIBITOR
WOS研究方向Biochemistry & Molecular Biology
语种英语
WOS记录号WOS:000672866400391
出版者ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/309403]  
专题新药研究国家重点实验室
通讯作者Xu, Yichen; Zhao, Quan
作者单位1.Nanjing Univ, State Key Lab Pharmaceut Biotechnol, Dept Hematol,Sch Life Sci, Affiliated Drum Tower Hosp,Med Sch,China Australi, Nanjing, Peoples R China;
2.Univ Calif San Francisco, Dept Urol, San Francisco, CA 94110 USA;
3.Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA;
4.Chinese Acad Sci, Drug Discovery & Design Ctr, Shanghai Inst Mat Med, CAS Key Lab Receptor Res,State Key Lab Drug Res, Shanghai, Peoples R China;
5.Zhejiang Univ, Coll Pharmaceut Sci, Zhejiang Prov Key Lab Anticanc Drug Res, Hangzhou, Peoples R China
推荐引用方式
GB/T 7714		 Wang, Ying,Li, Xinyu,Ge, Jingru,et al. The methyltransferase PRMT1 regulates γ-globin translation[J]. JOURNAL OF BIOLOGICAL CHEMISTRY,2021,296:100417.
APA Wang, Ying.,Li, Xinyu.,Ge, Jingru.,Liu, Ming.,Pang, Xiaming.,...&Zhao, Quan.(2021).The methyltransferase PRMT1 regulates γ-globin translation.JOURNAL OF BIOLOGICAL CHEMISTRY,296,100417.
MLA Wang, Ying,et al."The methyltransferase PRMT1 regulates γ-globin translation".JOURNAL OF BIOLOGICAL CHEMISTRY 296(2021):100417.

入库方式： OAI收割

来源：上海药物研究所

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