Abstract
The sequence context surrounding the AUG start codon of an open reading frame - the ‘Kozak sequence’ - affects the probability with which a scanning ribosome will recognize the start codon and start translating there. A significant number of transcripts in animals such as Drosophila contain weak Kozak sequences. This is predicted to cause constitutively low translation of these transcripts. We study here the additional possibility that these mRNAs have weak Kozak sequences to allow for the regulation of their translation in response to stress or altered cellular signaling. We find that transcripts with weak Kozak sequences are less sensitive to drops in global elongation rates and more sensitive to drops in global initiation rates compared to transcripts with strong Kozak sequences. This provides a mechanism by which changes in these global translation parameters differentially affect different pools of mRNAs depending on their Kozak sequence, thereby shaping the proteome. Interestingly, mRNAs with weak Kozak sequences are enriched for genes involved in neurobiology, suggesting that they constitute a functional group that can be translationally co-regulated.
Highlights
Regulation of protein translation is a key step in the control of gene expression[1]
Translation rates have traditionally been thought to be regulated either globally, or in an mRNA specific manner. mRNA-specific regulation is achieved by the presence of structural or sequence motifs on the mRNA, whereas more global changes in translation are usually due to changes in initiation factor activity[2,3]
We find that when global elongation rates are reduced in a cell, mRNAs with weak Kozak sequences are relatively refractory, dropping less in their translation compared to mRNAs with strong Kozak sequences
Summary
Regulation of protein translation is a key step in the control of gene expression[1]. Recent genome-wide studies, have shown that even ‘global’ mechanisms can differentially affect specific classes of mRNAs and thereby shape the proteome[4,5,6] Which of these changes in global translation parameters lead to differential effects on subsets of mRNAs, and how this is achieved, are topics of current research. When initiation rates are reduced, mRNAs with weak Kozak sequences are more sensitive, dropping more in their translation compared to mRNAs with strong Kozak sequences This interplay between global initiation and elongation rates via the Kozak sequence identifies how these ‘global’ regulatory mechanisms differentially affect different mRNAs, thereby shaping the proteome. This will likely be important for our understanding of how cells respond to stresses or environmental conditions that affect these global translation parameters
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