Structural insight into autoinhibition and histone H3-induced activation of DNMT3A
文献类型：期刊论文
| 作者 | Guo, X; Wang, L; Li, J; Ding, ZY; Xiao, JX; Yin, XT; He, S; Shi, P; Dong, LP; Li, GH |
| 刊名 | NATURE
 |
| 出版日期 | 2015 |
| 卷号 | 517期号:7536页码:640-U281 |
| 通讯作者 | Xu, YH (reprint author), Fudan Univ, Shanghai Med Coll, Inst Biomed Sci, Shanghai Canc Ctr, Shanghai 200032, Peoples R China.,xuyh@fudan.edu.cn |
| 英文摘要 | DNA methylation is an important epigenetic modification that is essential for various developmental processes through regulating gene expression, genomic imprinting, and epigenetic inheritance(1-5). Mammalian genomic DNA methylation is established during embryogenesis by de novo DNA methyltransferases, DNMT3A and DNMT3B(6-8), and the methylation patterns vary with developmental stages and cell types(9-12). DNAmethyltransferase 3-like protein (DNMT3L) is a catalytically inactive paralogue of DNMT3 enzymes, which stimulates the enzymatic activity of Dnmt3a(13). Recent studies have established a connection between DNA methylation and histone modifications, and revealed a histone-guided mechanism for the establishment of DNA methylation(14). The ATRX-DNMT3-DNMT3L (ADD) domain of Dnmt3a recognizes unmethylated histone H3 (H3K4me0)(15-17). The histone H3 tail stimulates the enzymatic activity of Dnmt3a in vitro(17,18), whereas the molecular mechanism remains elusive. Here we show that DNMT3A exists in an autoinhibitory form and that the histone H3 tail stimulates its activity in a DNMT3L-independent manner. We determine the crystal structures of DNMT3A-DNMT3L (autoinhibitory form) and DNMT3A-DNMT3L-H3 (active form) complexes at 3.82 and 2.90 angstrom resolution, respectively. Structural and biochemical analyses indicate that the ADD domain of DNMT3A interacts with and inhibits enzymatic activity of the catalyticdomain (CD) through blocking its DNA-binding affinity. HistoneH3(but not H3K4me3) disrupts ADD-CD interaction, induces a large movement of the ADD domain, and thus releases the autoinhibition of DNMT3A. The finding adds another layer of regulation of DNA methylation to ensure that the enzyme is mainly activated at proper targeting loci when unmethylated H3K4 is present, and strongly supports a negative correlation between H3K4me3 and DNA methylation across the mammalian genome(9,10,19,20). Our study provides a new insight into an unexpected autoinhibition and histone H3-induced activation of the de novo DNA methyltransferase after its initial genomic positioning. |
| 学科主题 | Science & Technology - Other Topics |
| 类目[WOS] | Multidisciplinary Sciences |
| 关键词[WOS] | DE-NOVO METHYLATION ; DNA METHYLATION ; MAMMALIAN DEVELOPMENT ; RECOMBINANT HISTONES ; HIGH-RESOLUTION ; METHYLTRANSFERASE ; PATTERNS ; EXPRESSION ; SOFTWARE ; GENOME |
| 收录类别 | SCI |
| 语种 | 英语 |
| WOS记录号 | WOS:000348775000049 |
| 版本 | 出版稿 |
| 源URL | [http://202.127.25.143/handle/331003/103]  |
| 专题 | 上海生化细胞研究所_上海生科院生化细胞研究所 |
| 推荐引用方式 GB/T 7714 | Guo, X,Wang, L,Li, J,et al. Structural insight into autoinhibition and histone H3-induced activation of DNMT3A[J]. NATURE,2015,517(7536):640-U281. |
| APA | Guo, X.,Wang, L.,Li, J.,Ding, ZY.,Xiao, JX.,...&Xu, YH.(2015).Structural insight into autoinhibition and histone H3-induced activation of DNMT3A.NATURE,517(7536),640-U281. |
| MLA | Guo, X,et al."Structural insight into autoinhibition and histone H3-induced activation of DNMT3A".NATURE 517.7536(2015):640-U281. |
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