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

N6-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 previousl...

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Main Authors: Zhou, You (Author) , Ćorović, Miona (Author) , Hoch-Kraft, Peter (Author) , Meiser, Nathalie (Author) , Mesitov, Mikhail (Author) , Körtel, Nadine (Author) , Back, Hannah (Author) , Naarmann-de Vries, Isabel S. (Author) , Katti, Kritika (Author) , Obrdlík, Aleš (Author) , Busch, Anke (Author) , Dieterich, Christoph (Author) , Vaňáčová, Štěpánka (Author) , Hengesbach, Martin (Author) , Zarnack, Kathi (Author) , König, Julian (Author)
Format: Article (Journal)
Language:English
Published: 5 December 2024
In: Molecular cell
Year: 2024, Volume: 84, Issue: 23, Pages: 4576-4593.e12
ISSN:1097-4164
DOI:10.1016/j.molcel.2024.10.033
Online Access:Verlag, kostenfrei, Volltext: https://doi.org/10.1016/j.molcel.2024.10.033
Verlag, kostenfrei, Volltext: https://www.sciencedirect.com/science/article/pii/S1097276524008736
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Author Notes:You Zhou, Miona Ćorović, Peter Hoch-Kraft, Nathalie Meiser, Mikhail Mesitov, Nadine Körtel, Hannah Back, Isabel S. Naarmann-de Vries, Kritika Katti, Aleš Obrdlík, Anke Busch, Christoph Dieterich, Štěpánka Vaňáčová, Martin Hengesbach, Kathi Zarnack, and Julian König
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Summary:N6-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.
Item Description:Online verfügbar: 21. November 2024, Artikelversion: 5. Dezember 2024
Gesehen am 04.06.2025
Physical Description:Online Resource
ISSN:1097-4164
DOI:10.1016/j.molcel.2024.10.033

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