文献类型：期刊文献

英文题名：DPY30 acts as an ASH2L-specific stabilizer to stimulate the enzyme activity of MLL family methyltransferases on different substrates

作者：Zhao, Lijie[1,2];Huang, Naizhe[1,2];Mencius, Jun[3];Li, Yanjing[3];Xu, Ying[1];Zheng, Yongxin[3];He, Wei;Li, Na[4];Zheng, Jun;Zhuang, Min[5];Quan, Shu[3,6];Chen, Yong[1,2,5]

机构：[1]Chinese Acad Sci, Shanghai Inst Biochem & Cell Biol, Natl Ctr Prot Sci Shanghai, Ctr Excellence Mol Cell Sci, Shanghai 200031, Peoples R China;[2]Univ Chinese Acad Sci, Beijing 100049, Peoples R China;[3]East China Univ Sci & Technol, Shanghai Collaborat Innovat Ctr Biomfg SCICB, State Key Lab Bioreactor Engn, Shanghai 200237, Peoples R China;[4]Chinese Acad Sci, Shanghai Adv Res Inst, Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China;[5]ShanghaiTech Univ, Sch Life Sci & Technol, 100 Haike Rd, Shanghai 201210, Peoples R China;[6]Shanghai Frontiers Sci Ctr Optogenet Tech Cell Met, Shanghai 200237, Peoples R China

年份：2022

卷号：25

期号：9

外文期刊名：ISCIENCE

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000861134500003)】；

基金：We thank the staff members of the Large-scale Protein Preparation System and the Mass Spectrometry System at the National Facility for Protein Science Shanghai (NFPS) for providing technical support. We thank the staff from the BL19U2 beamlines of the National Facility for Protein Science Shanghai (NFPS) at Shanghai Synchrotron Radiation Facility (SSRF) for SAXS data collection. We thank AMAX Information Technology (Shanghai) Co., Ltd. for hardware support .Figure 7C was drawn by Fig draw (www.figdraw.com). This work was supported by grants from the Strategic Priority Research Program of the Chinese Academy of Sciences (XDB37010303 to Y.C.), Shanghai Pilot Program for Basic Research from Chinese Academy of Science, Shanghai Branch (JCYJ-SHFY-2022-008 to Y.C.), the National Natural Science Foundation of China (31670748, 31970576 to Y.C., 31670802, 32171269 to Q.S., and 32071195, 31900934 to Y.L.), a grant from Shanghai Frontiers Science Center of Optogenetic Techniques for Cell Metabolism (Shanghai Municipal Education Commission, grant 2021 Sci & Tech 03-28), the Young Elite Scientist Sponsorship Program by China Association for Science and Technology (YESS20170198 to Y.L.), and the National Postdoctoral Program for Innovative Talents (BX201700263 to Y.L.).

语种：英文

摘要：Dumpy-30 (DPY30) is a conserved component of the mixed lineage leukemia (MLL) family complex and is essential for robust methyltransferase activity of MLL complexes. However, the biochemical role of DPY30 in stimulating methyl-transferase activity of MLL complexes remains elusive. Here, we demonstrate that DPY30 plays a crucial role in regulating MLL1 activity through two com-plementary mechanisms: A nucleosome-independent mechanism and a nucleo-some-specific mechanism. DPY30 functions as an ASH2L-specific stabilizer to increase the stability of ASH2L and enhance ASH2L-mediated interactions. As a result, DPY30 promotes the compaction and stabilization of the MLL1 complex, consequently increasing the HKMT activity of the MLL1 complex on diverse sub-strates. DPY30-stabilized ASH2L further acquires additional interfaces with H3 and nucleosomal DNA, thereby boosting the methyltransferase activity of the MLL1 complex on nucleosomes. These results collectively highlight the crucial and conserved roles of DPY30 in the complex assembly and activity regulation of MLL family complexes.