Mammalian RNA Decay Pathways Are Highly Specialized and Widely Linked to Translation

RNA decay is crucial for mRNA turnover and surveillance and misregulated in many diseases. This complex system is challenging to study, particularly in mammals, where it remains unclear whether decay pathways perform specialized versus redundant roles. Cytoplasmic pathways and links to translation are particularly enigmatic. By directly profiling decay factor targets and normal versus aberrant translation in mouse embryonic stem cells (mESCs), we uncovered extensive decay pathway specialization and crosstalk with translation. XRN1 (5′-3′) mediates cytoplasmic bulk mRNA turnover whereas SKIV2L (3′-5′) is universally recruited by ribosomes, tackling aberrant translation and sometimes modulating mRNA abundance. Further exploring translation surveillance revealed AVEN and FOCAD as SKIV2L interactors. AVEN prevents ribosome stalls at structured regions, which otherwise require SKIV2L for clearance. This pathway is crucial for histone translation, upstream open reading frame (uORF) regulation, and counteracting ribosome arrest on small ORFs. In summary, we uncovered key targets, components, and functions of mammalian RNA decay pathways and extensive coupling to translation. [Display omitted] •Global profiling of mRNA decay pathways and aberrant translation events in mESCs•XRN1 mediates mRNA turnover, whereas SKIV2L acts widely in translation surveillance•AVEN interacts with ribosomes and the Ski complex and counteracts ribosome stalling•Histone mRNAs, uORFs, and small ORFs are key targets of SKIV2L and AVEN Tuck, Rankova, et al. globally profile mRNA decay and aberrant translation events in mouse embryonic stem cells, finding that mRNA decay pathways perform specialized roles rather than acting redundantly. They uncover widespread crosstalk between mRNA decay and translation and identify AVEN as a factor that counteracts ribosome stalling.