Abstract
No-go Decay (NGD) is a process that has evolved to deal with stalled ribosomes resulting from structural blocks or aberrant mRNAs. The process is distinguished by an endonucleolytic cleavage prior to degradation of the transcript. While many of the details of the pathway have been described, the identity of the endonuclease remains unknown. Here we identify residues of the small subunit ribosomal protein Rps3 that are important for NGD by affecting the cleavage reaction. Mutation of residues within the ribosomal entry tunnel that contact the incoming mRNA leads to significantly reduced accumulation of cleavage products, independent of the type of stall sequence, and renders cells sensitive to damaging agents thought to trigger NGD. These phenotypes are distinct from those seen in combination with other NGD factors, suggesting a separate role for Rps3 in NGD. Conversely, ribosomal proteins ubiquitination is not affected by rps3 mutations, indicating that upstream ribosome quality control (RQC) events are not dependent on these residues. Together, these results suggest that Rps3 is important for quality control on the ribosome and strongly supports the notion that the ribosome itself plays a central role in the endonucleolytic cleavage reaction during NGD.
Highlights
The elongation phase of translation is an imperfect process, during which the ribosome moves with irregular speed along the mRNA template [1]
That organisms evolved pathways to resolve these valuable stuck ribosomes. This process is called no-go decay (NGD) because it is coupled with decay of mRNAs that are associated with ribosomes that do not ‘go’
We show that the ribosome itself is very central to the cleavage reaction
Summary
The elongation phase of translation is an imperfect process, during which the ribosome moves with irregular speed along the mRNA template [1]. Regardless of the underlying mechanism, the fluctuating rate of protein synthesis along an mRNA molecule appears to serve important biological functions such as promoting appropriate co-translational protein folding and ensuring that the encoded protein is targeted to the correct destination in the cell [7,8,9,10,11,12]. In contrast to this “programmed” regulation of ribosome traffic, the ribosome often encounters unwanted obstacles that severely hinder its progression and in some cases stall protein synthesis all together [13, 14]. The resulting deadenylated 5’-end and uncapped 3’-end pieces are rapidly degraded by the exosome and Xrn, respectively [3, 15,16,17]
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