Zhao Lijie, Huang Naizhe, Mencius Jun, Li Yanjing, Xu Ying, Zheng Yongxin, He Wei, Li Na, Zheng Jun, Zhuang Min, Quan Shu, Chen Yong
State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, Shanghai Institute of Biochemistry and Cell Biology, Center for Excellence in Molecular Cell Science, Chinese Academy of Sciences, Shanghai 200031, China.
University of Chinese Academy of Sciences, Beijing 100049, China.
iScience. 2022 Aug 16;25(9):104948. doi: 10.1016/j.isci.2022.104948. eCollection 2022 Sep 16.
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 methyltransferase activity of MLL complexes remains elusive. Here, we demonstrate that DPY30 plays a crucial role in regulating MLL1 activity through two complementary mechanisms: A nucleosome-independent mechanism and a nucleosome-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 substrates. 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.
矮小30（DPY30）是混合谱系白血病（MLL）家族复合物的一个保守组分，对于MLL复合物强大的甲基转移酶活性至关重要。然而，DPY30在刺激MLL复合物甲基转移酶活性方面的生化作用仍不清楚。在此，我们证明DPY30通过两种互补机制在调节MLL1活性中起关键作用：一种不依赖核小体的机制和一种核小体特异性机制。DPY30作为ASH2L特异性稳定剂发挥作用，以增加ASH2L的稳定性并增强ASH2L介导的相互作用。结果，DPY30促进MLL1复合物的压缩和稳定，从而增加MLL1复合物对多种底物的组蛋白赖氨酸甲基转移酶（HKMT）活性。DPY30稳定的ASH2L进一步获得与H3和核小体DNA的额外界面，从而增强MLL1复合物对核小体的甲基转移酶活性。这些结果共同突出了DPY30在MLL家族复合物的复合物组装和活性调节中的关键和保守作用。
