The N6-methyladenosine (m6A) modification regulates mRNA stability and translation. Here, we show that transcriptomic m6A modification can be dynamic and the m6A reader protein YTH N6-methyladenosine RNA binding protein 2 (YTHDF2) promotes mRNA decay during cell cycle. Depletion of YTHDF2 in HeLa cells leads to the delay of mitotic entry due to overaccumulation of negative regulators of cell cycle such as Wee1-like protein kinase (WEE1). We demonstrate that WEE1 transcripts contain m6A modification, which promotes their decay through YTHDF2. Moreover, we found that YTHDF2 protein stability is dependent on cyclin-dependent kinase 1 (CDK1) activity. Thus, CDK1, YTHDF2, and WEE1 form a feedforward regulatory loop to promote mitotic entry. We further identified Cullin 1 (CUL1), Cullin 4A (CUL4A), damaged DNA-binding protein 1 (DDB1), and S-phase kinase-associated protein 2 (SKP2) as components of E3 ubiquitin ligase complexes that mediate YTHDF2 proteolysis. Our study provides insights into how cell cycle mediators modulate transcriptomic m6A modification, which in turn regulates the cell cycle.

中文翻译：

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YTHDF2 促进有丝分裂进入并受细胞周期介质调节。

N6-甲基腺苷 (m6A) 修饰调节 mRNA 稳定性和翻译。在这里，我们表明转录组 m6A 修饰可以是动态的，并且 m6A 阅读器蛋白 YTH N6-甲基腺苷 RNA 结合蛋白 2 (YTHDF2) 在细胞周期中促进 mRNA 衰减。由于细胞周期负调节因子如 Wee1 样蛋白激酶 (WEE1) 的过度积累，HeLa 细胞中 YTHDF2 的消耗导致有丝分裂进入延迟。我们证明 WEE1 转录本包含 m6A 修饰，通过 YTHDF2 促进它们的衰变。此外，我们发现 YTHDF2 蛋白的稳定性取决于细胞周期蛋白依赖性激酶 1 (CDK1) 的活性。因此，CDK1、YTHDF2 和 WEE1 形成前馈调节回路以促进有丝分裂进入。我们进一步鉴定了 Cullin 1 (CUL1)、Cullin 4A (CUL4A)、受损的 DNA 结合蛋白 1 (DDB1)、和 S 期激酶相关蛋白 2 (SKP2) 作为 E3 泛素连接酶复合物的组分，介导 YTHDF2 蛋白水解。我们的研究提供了关于细胞周期介质如何调节转录组 m6A 修饰的见解，后者反过来调节细胞周期。