The m6A reader protein YTHDC2 interacts with the small ribosomal subunit and the 5′–3′ exoribonuclease XRN1
- Jens Kretschmer1,
- Harita Rao2,
- Philipp Hackert1,
- Katherine E. Sloan1,
- Claudia Höbartner2,3 and
- Markus T. Bohnsack1,4
- 1Department of Molecular Biology, University Medical Centre Göttingen, 37073 Göttingen, Germany
- 2Institute for Organic and Biomolecular Chemistry, Georg-August-University, 37077 Göttingen, Germany
- 3Institute for Organic Chemistry, University Würzburg, 97074 Würzburg, Germany
- 4Göttingen Center for Molecular Biosciences, Georg-August-University, 37073 Göttingen, Germany
- Corresponding author: markus.bohnsack{at}med.uni-goettingen.de
Abstract
N6-methyladenosine (m6A) modifications in RNAs play important roles in regulating many different aspects of gene expression. While m6As can have direct effects on the structure, maturation, or translation of mRNAs, such modifications can also influence the fate of RNAs via proteins termed “readers” that specifically recognize and bind modified nucleotides. Several YTH domain-containing proteins have been identified as m6A readers that regulate the splicing, translation, or stability of specific mRNAs. In contrast to the other YTH domain-containing proteins, YTHDC2 has several defined domains and here, we have analyzed the contribution of these domains to the RNA and protein interactions of YTHDC2. The YTH domain of YTHDC2 preferentially binds m6A-containing RNAs via a conserved hydrophobic pocket, whereas the ankyrin repeats mediate an RNA-independent interaction with the 5′–3′ exoribonuclease XRN1. We show that the YTH and R3H domains contribute to the binding of YTHDC2 to cellular RNAs, and using crosslinking and analysis of cDNA (CRAC), we reveal that YTHDC2 interacts with the small ribosomal subunit in close proximity to the mRNA entry/exit sites. YTHDC2 was recently found to promote a “fast-track” expression program for specific mRNAs, and our data suggest that YTHDC2 accomplishes this by recruitment of the RNA degradation machinery to regulate the stability of m6A-containing mRNAs and by utilizing its distinct RNA-binding domains to bridge interactions between m6A-containing mRNAs and the ribosomes to facilitate their efficient translation.
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Footnotes
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Article is online at http://www.rnajournal.org/cgi/doi/10.1261/rna.064238.117.
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Freely available online through the RNA Open Access option.
- Received September 27, 2017.
- Accepted June 26, 2018.
This article, published in RNA, is available under a Creative Commons License (Attribution-NonCommercial 4.0 International), as described at http://creativecommons.org/licenses/by-nc/4.0/.