October 1, 1992Genes & Development179 citationsOpen Access
Evidence for instability of mRNAs containing AUUUA motifs mediated through translation-dependent assembly of a > 20S degradation complex.
Key Result
The presence of GM-CSF AUUUA motifs in an otherwise stable beta-globin mRNA results in a 50-fold decrease in accumulated mRNA level, requiring active translation and assembly of a >20S complex.
Structured PICO
P
Population
mRNAs containing AUUUA motifs, specifically GM-CSF mRNA and beta-globin mRNA constructs
I
Intervention
Presence of AUUUA motifs in the 3'-untranslated region and active translation
C
Comparator
Stable beta-globin mRNA without AUUUA motifs, or conditions without active translation
O
Outcome
RNA instability and formation of a >20S degradation complexsurrogate
The study demonstrates that mRNA instability mediated by AUUUA motifs requires active translation and involves the assembly of a large (>20S) degradation complex.
Main Result
Effect estimate: 50-fold decrease
Abstract
Many short-lived mRNAs, including those encoding lymphokines, cytokines, and proto-oncogenes, contain an AU-rich sequence in their 3'-untranslated regions. These AU domains and, more specifically, AUUUA motifs within them, are widely thought to mediate the extreme instability of the corresponding mRNAs. This is most clearly true for granulocyte monocyte colony stimulating factor (GM-CSF) mRNA whose AUUUA motifs are conserved phylogenetically and whose presence in an otherwise stable beta-globin mRNA results in a 50-fold decrease in accumulated mRNA level. We show that RNA instability conferred by the GM-CSF AU motif requires the mRNA to be actively translated and the AU motif to be within the 3'-untranslated region. By analysis of the sedimentation characteristics, we identify a large (> 20S), divalent cation-independent complex found only on unstable RNAs. Like instability, complex formation (1) is dependent on translation of the RNA, (2) requires intact AUUUA motifs, and (3) is blocked by ribosome translocation across the AU-rich motif. We propose that RNA instability mediated by the AU motif is achieved through translation-dependent assembly of this large mRNA-destabilizing complex.