Abstract
SummaryRNA 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.
Highlights
RNA decay ensures steady-state mRNA expression, eliminates aberrant transcripts, and remodels the transcriptome upon changing conditions (Bresson et al, 2017; Perez-Ortın et al, 2013; Sohrabi-Jahromi et al, 2019; Tuck and Tollervey, 2013)
RNA decay is crucial for mRNA turnover and surveillance and misregulated in many diseases
This complex system is challenging to study, in mammals, where it remains unclear whether decay pathways perform specialized versus redundant roles
Summary
RNA decay ensures steady-state mRNA expression, eliminates aberrant transcripts, and remodels the transcriptome upon changing conditions (Bresson et al, 2017; Perez-Ortın et al, 2013; Sohrabi-Jahromi et al, 2019; Tuck and Tollervey, 2013). MRNAs are mainly degraded 30–50 by the exosome complex, assisted by factors including the helicase Mtr (MTR4) (Kilchert et al, 2016; LaCava et al, 2005; Mitchell et al, 1997; Schmid and Jensen, 2018). Cytoplasmic exosome activity requires the Ski complex (Anderson and Parker, 1998), comprising the scaffold Ski (TTC37), two copies of Ski (WDR61), and the helicase Ski (SKIV2L). XRN1 is downregulated in osteosarcoma (Pashler et al, 2016), exosome mutations are linked to cancer (Robinson et al, 2015) and neurological disorders (Morton et al, 2018), and Ski complex impairment causes a congenital bowl disorder (Fabre et al, 2012; Hartley et al, 2010)
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