Abstract
Most eukaryotic mRNAs are recruited to the ribosome by recognition of a 5ʹ m7GpppN cap. 30 years of genetic and biochemical evidence point to a role for interaction between the 5ʹ cap-interacting factors and the 3ʹ poly(A)-binding protein in bringing the ends of the mRNA into close proximity and promoting both translation and stability of the mRNA, in a form known as the “closed loop”. However, the results of recent RNA–protein interaction studies suggest that not all mRNAs have equal access to the closed loop factors. Furthermore, association with closed loop factors appears to be highly biased towards mRNAs with short open reading frames, echoing the trend for higher translation of short mRNAs that has been observed in many eukaryotes. We recently reported that the ribosomal signaling scaffold protein RACK1 promotes the efficient translation of short mRNAs that strongly associate with the closed loop factors. Here, we discuss the implications of these observations with respect to translational control and suggest avenues through which the universality of the closed loop in eukaryotic translation could be revisited.
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Notes
The literature is inconsistent regarding the magnitude of stimulation required for synergy. In many cases, stimulation by the combined action of the cap and poly(A) tail that is greater than the sum of their independent effects is described as “synergy”. We favor the null hypothesis that the combination of independent effects will produce stimulation equal to the product of their individual effects. Thus, only enhancement greater than the product constitutes synergy.
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Acknowledgements
We thank Allan Jacobson, David Bartel, and members of the Gilbert lab for helpful discussions. This work was supported by the National Institutes of Health (GM094303) to WVG and in part by the NIH Pre-Doctoral Training Grant T32GM007287.
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Communicated by M. Kupiec.
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Thompson, M.K., Gilbert, W.V. mRNA length-sensing in eukaryotic translation: reconsidering the “closed loop” and its implications for translational control. Curr Genet 63, 613–620 (2017). https://doi.org/10.1007/s00294-016-0674-3
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DOI: https://doi.org/10.1007/s00294-016-0674-3