m6A sites in the coding region trigger translation-dependent mRNA decay

N<sup>6</sup>-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. Here, using human cells, we reveal that m6A sites in the coding sequence (CDS) trigger CDS-m6A decay (CMD), a pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors. Mechanistically, CMD depends on translation, whereby m6A deposition in the CDS triggers ribosome pausing and transcript destabilization. The subsequent decay involves the translocation of the CMD target transcripts to processing bodies (P-bodies) and recruitment of the m6A reader protein YT521-B homology domain family protein 2 (YTHDF2). Our findings highlight CMD as a previously unknown pathway, which is particularly important for controlling the expression of developmental regulators and retrogenes.

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Publication Details

Journal
Molecular Cell
Published
2024-11-21
DOI
https://doi.org/10.1016/j.molcel.2024.10.033
Citations
65
Primary Topic
RNA modifications and cancer
Type
article
Field-Weighted Citation Impact
15.20

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article

m6A sites in the coding region trigger translation-dependent mRNA decay

Mikhail Mesitov, You Zhou, Kattesh V. Katti, Nadine Körtel et al.
65 citations
Molecular Cell
RNA modifications and cancer
15.20
article

m6A sites in the coding region trigger translation-dependent mRNA decay

Mikhail Mesitov, You Zhou, Kattesh V. Katti, Nadine Körtel, Aleš Obrdlík, Nathalie Meiser, Štěpánka Vaňáčová, Anke Busch, H. Back, Isabel S. Naarmann‐de Vries, Kathi Zarnack, Peter Hoch-Kraft, Julian König, Martin Hengesbach, Christoph Dieterich, Miona Ćorović
article en
65 citations

Abstract

N<sup>6</sup>-Methyladenosine (m6A) is the predominant internal RNA modification in eukaryotic messenger RNAs (mRNAs) and plays a crucial role in mRNA stability. Here, using human cells, we reveal that m6A sites in the coding sequence (CDS) trigger CDS-m6A decay (CMD), a pathway that is distinct from previously reported m6A-dependent degradation mechanisms. Importantly, CDS m6A sites act considerably faster and more efficiently than those in the 3' untranslated region, which to date have been considered the main effectors. Mechanistically, CMD depends on translation, whereby m6A deposition in the CDS triggers ribosome pausing and transcript destabilization. The subsequent decay involves the translocation of the CMD target transcripts to processing bodies (P-bodies) and recruitment of the m6A reader protein YT521-B homology domain family protein 2 (YTHDF2). Our findings highlight CMD as a previously unknown pathway, which is particularly important for controlling the expression of developmental regulators and retrogenes.

Molecular CellVol. 84(23)
Goethe University Frankfurt (DE), Central European Institute of Technology (CZ), Institute of Molecular Biology (DE)
European Commission, Deutsche Forschungsgemeinschaft, Ministerstvo Školství, Mládeže a Tělovýchovy
Zero hunger
Openalex Percentile: Top 0%
RNA modifications and cancer
15.20
DOIOpen Access PDFOpenAlex
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