PUBLICATION
The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition
- Authors
- Li, L., Krasnykov, K., Homolka, D., Gos, P., Mendel, M., Fish, R.J., Pandey, R.R., Pillai, R.S.
- ID
- ZDB-PUB-220320-9
- Date
- 2022
- Source
- Molecular Cell 82(9): 1678-1690.e12 (Journal)
- Registered Authors
- Fish, Richard
- Keywords
- DExH helicase, MEIOC, RBM46, RNA helicase, XRN1, YTH, YTHDC2, m(6)A, oogenesis, spermatogenesis
- MeSH Terms
-
- Animals
- Fertility/genetics
- Mammals/metabolism
- Meiosis
- Mice
- RNA/genetics
- RNA Helicases*/genetics
- RNA Helicases*/metabolism
- Zebrafish*/genetics
- PubMed
- 35305312 Full text @ Mol. Cell
Citation
Li, L., Krasnykov, K., Homolka, D., Gos, P., Mendel, M., Fish, R.J., Pandey, R.R., Pillai, R.S. (2022) The XRN1-regulated RNA helicase activity of YTHDC2 ensures mouse fertility independently of m6A recognition. Molecular Cell. 82(9):1678-1690.e12.
Abstract
The functional consequence of N6-methyladenosine (m6A) 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 m6A-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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping