FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression
FTO Demethylates Cyclin D1 mRNA and Controls Cell-Cycle Progression
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DOI：
10.1016/j.celrep.2020.03.028
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发表时间：
2020-04-07
期刊：
影响因子：
8.8
通讯作者：
Tomizawa, Kazuhito
中科院分区：
文献类型：
--
作者：
Hirayama, Mayumi;Wei, Fan-Yan;Tomizawa, Kazuhito
N-6-甲基腺苷（m（6）A）修饰是mRNA中控制基本生物学过程（包括细胞增殖）的主要化学修饰。在此，我们证明了脂肪量和肥胖相关（FTO）去甲基化m（6）A修饰的细胞周期蛋白D1，G1期进展的关键调节因子和控制细胞增殖在体外和体内。FTO缺失上调细胞周期蛋白D1 m（6）A修饰，进而加速细胞周期蛋白D1 mRNA的降解，导致G1期进展受损。m（6）细胞周期蛋白D1的修饰以细胞周期依赖性方式振荡; m（6）A水平在G1期受到抑制，在其他期得到增强。G1期低m（6）A水平与FTO从胞质中的核转位有关。此外，FTO的核质穿梭受酪蛋白激酶II介导的FTO磷酸化的调节。我们的研究结果强调了m（6）A在调节细胞周期蛋白D1 mRNA稳定性中的作用，并为细胞周期调节增加了另一层复杂性。
N-6-Methyladenosine (m(6)A) modification is the major chemical modification in mRNA that controls fundamental biological processes, including cell proliferation. Herein, we demonstrate that fat mass and obesity-associated (FTO) demethylates m(6)A modification of cyclin D1, the key regulator for G1 phase progression and controls cell proliferation in vitro and in vivo. FTO depletion upregulates cyclin D1 m(6)A modification, which in turn accelerates the degradation of cyclin D1 mRNA, leading to the impairment of G1 progression. m(6)A modification of cyclin D1 oscillates in a cell-cycle-dependent manner; m(6)A levels are suppressed during the G1 phase and enhanced during other phases. Low m(6)A levels during G1 are associated with the nuclear translocation of FTO from the cytosol. Furthermore, nucleocytoplasmic shuttling of FTO is regulated by casein kinase II-mediated phosphorylation of FTO. Our results highlight the role of m(6)A in regulating cyclin D1 mRNA stability and add another layer of complexity to cell-cycle regulation.