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Biochemical Insights Into the Conserved Interactions of NMD Factors From Budding Yeast to Humans.

Nadia Ruiz-Gutierrez·Marc Graille·Hervé Le Hir·Cosmin Saveanu
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Abstract

Nonsense-mediated mRNA decay (NMD) is one of the most extensively studied pathways of cytoplasmic mRNA degradation. It plays a critical role in diverse cellular processes by eliminating aberrant transcripts containing premature stop codons and by regulating the stability of physiological mRNAs. NMD factors were initially identified through genetic screens in S. cerevisiae (UPF1, 2, 3) and C. elegans (SMG-1, SMG5-7). Subsequent biochemical and genetic studies revealed the composition of NMD complexes and identified additional factors. A major protein hub for NMD is Upf1, an ATP-dependent RNA helicase that is part of two mutually exclusive NMD assemblies, the Upf1-Upf2-Upf3 complex and the Upf1-decapping complex, which contains the decapping enzyme and its co-factors. Here, we discuss recent findings, primarily from budding yeast, on the protein-protein interactions driving NMD complexes dynamics and their similarities to human NMD. Together, the N-terminal cysteine and histidine rich (CH) and helicase domains (HD) of Upf1 act as a hub for binding multiple partners. Upf1 is required for binding to NMD substrates and for the initiation of RNA degradation through decapping (yeast) or endonucleolytic hydrolysis (humans). We focus on the interplay between Upf2, Dcp2 and Nmd4 (yeast SMG6), which ensures the mutually exclusive formation of Upf1-bound subcomplexes modulating Upf1's affinity for RNA. Thus, the study of NMD factors interactions in different organisms sheds new light on the remarkable conservation of NMD molecular mechanisms.

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Nonsense Mediated mRNA DecayHumansRNA HelicasesAnimalsSaccharomyces cerevisiae ProteinsSaccharomyces cerevisiaeSaccharomycetalesRNA, MessengerProtein BindingNMDRNA decappingnonsense-mediated mRNA decayprotein interactionsJournal ArticleReview

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Nadia Ruiz-Gutierrez, Marc Graille, Hervé Le Hir, Cosmin Saveanu. 2026-03-10. Biochemical Insights Into the Conserved Interactions of NMD Factors From Budding Yeast to Humans.. https://doi.org/10.1016/j.jmb.2026.169751

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