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

Mol Cell. 2020 Mar 19;77(6):1222-1236.e13. doi: 10.1016/j.molcel.2020.01.007. Epub 2020 Feb 10.


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.

Keywords: AVEN; RNA; RNA decay; RNA degradation; RNA surveillance; SKIV2L; histones; ribosome; ribosome stalling; translation.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis Regulatory Proteins / physiology*
  • CRISPR-Cas Systems
  • DNA-Binding Proteins / physiology*
  • Exoribonucleases / physiology*
  • Gene Expression Regulation
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mouse Embryonic Stem Cells / cytology
  • Mouse Embryonic Stem Cells / metabolism*
  • Open Reading Frames
  • Protein Biosynthesis*
  • Proto-Oncogene Proteins / physiology
  • RNA Helicases / physiology*
  • RNA Stability*
  • RNA, Messenger / chemistry
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism*
  • Ribosomes / genetics
  • Ribosomes / metabolism


  • Apoptosis Regulatory Proteins
  • Aven protein, mouse
  • DNA-Binding Proteins
  • Proto-Oncogene Proteins
  • RNA, Messenger
  • Ski protein, mouse
  • Exoribonucleases
  • Xrn1 protein, mouse
  • RNA Helicases
  • SKIV2L2 protein, mouse