Hakai is required for stabilization of core components of the m(6)A mRNA methylation machinery.
Hakai is required for stabilization of core components of the m(6)A mRNA methylation machinery.
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DOI：
10.1038/s41467-021-23892-5
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发表时间：
2021-06-18
影响因子：
16.6
通讯作者：
Roignant JY
中科院分区：
文献类型：
--
作者：
Bawankar P;Lence T;Paolantoni C;Haussmann IU;Kazlauskiene M;Jacob D;Heidelberger JB;Richter FM;Nallasivan MP;Morin V;Kreim N;Beli P;Helm M;Jinek M;Soller M;Roignant JY
N6 - 甲基腺苷（m6A）是mRNA上最丰富的内部修饰，它影响mRNA代谢的大多数步骤，并参与多种生物学功能。先前在植物和哺乳动物细胞中发现E3泛素连接酶Hakai与m6A甲基化机制的组分形成复合物，但其确切功能仍有待研究。在此我们表明，Hakai是果蝇和人类细胞中甲基转移酶复合物的一个保守组分。在果蝇中，其缺失导致m6A水平降低以及包括性别决定在内的m6A依赖性功能改变。我们表明其泛素化结构域是二聚化以及与m6A机制的其他成员相互作用所必需的，而其催化活性则是可有可无的。最后，我们证明Hakai的缺失使甲基转移酶复合物的几个亚基不稳定，导致m6A沉积受损。我们的工作为m6A mRNA“书写器”复合物的机制增添了功能和分子层面的见解。
E3连接酶Hakai能够与m6A甲基化机制相互作用，但其功能仍不清楚。在此，作者表明Hakai是m6A甲基转移酶复合物的一个保守组分，并为其在果蝇中调节m6A水平的作用提供了功能和分子层面的见解。
N6-methyladenosine (m6A) is the most abundant internal modification on mRNA which influences most steps of mRNA metabolism and is involved in several biological functions. The E3 ubiquitin ligase Hakai was previously found in complex with components of the m6A methylation machinery in plants and mammalian cells but its precise function remained to be investigated. Here we show that Hakai is a conserved component of the methyltransferase complex in Drosophila and human cells. In Drosophila, its depletion results in reduced m6A levels and altered m6A-dependent functions including sex determination. We show that its ubiquitination domain is required for dimerization and interaction with other members of the m6A machinery, while its catalytic activity is dispensable. Finally, we demonstrate that the loss of Hakai destabilizes several subunits of the methyltransferase complex, resulting in impaired m6A deposition. Our work adds functional and molecular insights into the mechanism of the m6A mRNA writer complex. The E3 ligase Hakai can interact with the m6A methylation machinery but its function is still unclear. Here, the authors show that Hakai is a conserved component of the m6A methyltransferase complex and provide functional and molecular insights into its role in regulating m6A levels in Drosophila.
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影响因子：
16.6
作者：
Kan L;Grozhik AV;Vedanayagam J;Patil DP;Pang N;Lim KS;Huang YC;Joseph B;Lin CJ;Despic V;Guo J;Yan D;Kondo S;Deng WM;Dedon PC;Jaffrey SR;Lai EC
通讯作者：
Lai EC
影响因子：
64.8
作者：
Lence, Tina;Akhtar, Junaid;Roignant, Jean-Yves
通讯作者：
Roignant, Jean-Yves
DOI：
10.1073/pnas.1721371115
发表时间：
2018-06-05
影响因子：
11.1
作者：
Fustin JM;Kojima R;Itoh K;Chang HY;Ye S;Zhuang B;Oji A;Gibo S;Narasimamurthy R;Virshup D;Kurosawa G;Doi M;Manabe I;Ishihama Y;Ikawa M;Okamura H
通讯作者：
Okamura H
影响因子：
4.4
作者：
Cox, Juergen;Neuhauser, Nadin;Mann, Matthias
通讯作者：
Mann, Matthias
影响因子：
9.2
作者：
Aparicio, Luis A.;Valladares, Manuel;Blanco, Moises;Alonso, Guillermo;Figueroa, Angelica
通讯作者：
Figueroa, Angelica