| First Author | Li L | Year | 2022 |
| Journal | Mol Cell | Volume | 82 |
| Issue | 9 | Pages | 1678-1690.e12 |
| PubMed ID | 35305312 | Mgi Jnum | J:328765 |
| Mgi Id | MGI:7286131 | Doi | 10.1016/j.molcel.2022.02.034 |
| Citation | Li L, et al. (2022) The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m(6)A recognition. Mol Cell 82(9):1678-1690.e12 |
| abstractText | The functional consequence of N(6)-methyladenosine (m(6)A) RNA modification is mediated by "reader" proteins of the YTH family. YTH domain-containing 2 (YTHDC2) is essential for mammalian fertility, but its molecular function is poorly understood. Here, we identify U-rich motifs as binding sites of YTHDC2 on 3' UTRs of mouse testicular RNA targets. Although its YTH domain is an m(6)A-binder in vitro, the YTH point mutant mice are fertile. Significantly, the loss of its 3'-->5' RNA helicase activity causes mouse infertility, with the catalytic-dead mutation being dominant negative. Biochemical studies reveal that the weak helicase activity of YTHDC2 is enhanced by its interaction with the 5'-->3' exoribonuclease XRN1. Single-cell transcriptomics indicate that Ythdc2 mutant mitotic germ cells transition into meiosis but accumulate a transcriptome with mixed mitotic/meiotic identity that fail to progress further into meiosis. Finally, our demonstration that ythdc2 mutant zebrafish are infertile highlights its conserved role in animal germ cell development. |
