YTHDF2 Promotes Mitotic Entry and is Regulated by Cell Cycle Mediators

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by Qili Fei, Zhongyu Zou, Ian A. Roundtree, Hui-Lung Sun, Chuan He

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... Want to read more? You can find the complete article in the PLOS Biology Blog.

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