Zhu Bing, Zheng Yong, Pham Anh-Dung, Mandal Subhrangsu S, Erdjument-Bromage Hediye, Tempst Paul, Reinberg Danny
Howard Hughes Medical Institute, Division of Nucleic Acids Enzymology, Department of Biochemistry, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, 683 Hoes Lane, Piscataway, New Jersey 08854, USA.
Mol Cell. 2005 Nov 23;20(4):601-11. doi: 10.1016/j.molcel.2005.09.025.
In yeast, histone H2B monoubiquitination is a cotranscriptional event regulating histone H3 methylation at lysines 4 and 79. However, mammalian H2B monoubiquitination remains poorly understood. We report that in humans, the 600 kDa RNF20/40 complex is the E3 ligase and UbcH6 is the ubiquitin E2-conjugating enzyme for H2B-Lys120 monoubiquitination. RNF20 and RNF40 are both homologs of Bre1, the E3 ligase in the yeast case. UbcH6 physically interacts with RNF20/40 and with the hPAF complex. Formation of a trimeric complex with hPAF stimulates H2B monoubiquitination activity in vitro. Accordingly, UbcH6, RNF20/40, and the hPAF complex are recruited to transcriptionally active genes in vivo. RNF20 overexpression leads to elevated H2B monoubiquitination, subsequently higher levels of methylation at H3 lysines 4 and 79, and stimulation of HOX gene expression. In contrast, RNAi against the RNF20/40 complex or hPAF complex reduces H2B monoubiquitination, lowers methylation levels at H3 lysines 4 and 79, and represses HOX gene expression.
在酵母中，组蛋白H2B单泛素化是一种共转录事件，可调节赖氨酸4和79处的组蛋白H3甲基化。然而，哺乳动物的H2B单泛素化仍知之甚少。我们报告，在人类中，600 kDa的RNF20/40复合物是H2B赖氨酸120单泛素化的E3连接酶，UbcH6是泛素E2结合酶。RNF20和RNF40都是酵母中E3连接酶Bre1的同源物。UbcH6与RNF20/40以及hPAF复合物发生物理相互作用。与hPAF形成三聚体复合物可在体外刺激H2B单泛素化活性。因此，UbcH6、RNF20/40和hPAF复合物在体内被募集到转录活跃的基因上。RNF20的过表达导致H2B单泛素化升高，随后H3赖氨酸4和79处的甲基化水平更高，并刺激HOX基因表达。相反，针对RNF20/40复合物或hPAF复合物的RNA干扰会降低H2B单泛素化，降低H3赖氨酸4和79处的甲基化水平，并抑制HOX基因表达。
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