YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators.
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 ce...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2020-04-01
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| Series: | PLoS Biology |
| Online Access: | https://doi.org/10.1371/journal.pbio.3000664 |
| _version_ | 1818892442985824256 |
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| author | Qili Fei Zhongyu Zou Ian A Roundtree Hui-Lung Sun Chuan He |
| author_facet | Qili Fei Zhongyu Zou Ian A Roundtree Hui-Lung Sun Chuan He |
| author_sort | Qili Fei |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-19T17:56:47Z |
| format | Article |
| id | doaj.art-82ccdd9581b547038ec0d6319bdc2eb1 |
| institution | Directory Open Access Journal |
| issn | 1544-9173 1545-7885 |
| language | English |
| last_indexed | 2024-12-19T17:56:47Z |
| publishDate | 2020-04-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Biology |
| spelling | doaj.art-82ccdd9581b547038ec0d6319bdc2eb12022-12-21T20:11:48ZengPublic Library of Science (PLoS)PLoS Biology1544-91731545-78852020-04-01184e300066410.1371/journal.pbio.3000664YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators.Qili FeiZhongyu ZouIan A RoundtreeHui-Lung SunChuan HeThe 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.https://doi.org/10.1371/journal.pbio.3000664 |
| spellingShingle | Qili Fei Zhongyu Zou Ian A Roundtree Hui-Lung Sun Chuan He YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators. PLoS Biology |
| title | YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators. |
| title_full | YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators. |
| title_fullStr | YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators. |
| title_full_unstemmed | YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators. |
| title_short | YTHDF2 promotes mitotic entry and is regulated by cell cycle mediators. |
| title_sort | ythdf2 promotes mitotic entry and is regulated by cell cycle mediators |
| url | https://doi.org/10.1371/journal.pbio.3000664 |
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