GCN sensitive protein translation in yeast

PONE-D-20-12392

Dear Dr. Weir,

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #1: Yes

Reviewer #2: Yes

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Reviewer #2: Yes

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Reviewer #1: The paper by Barr et al. shows an elaborated example for research spanning various disciplines, bringing together molecular dynamics, bioinformatics and wet-lab biochemistry - each technically very thorough.

The conclusions drawn are well-based and elucidate a phenomenon so far little understood.

Reviewer #2: The manuscript by Barr et al. is devoted to the discovery and study of the mechanism of mRNA translation regulation, mediated by overrepresentation of GCN codons in the initial section of ORFs (so-called ramp region). The authors make a counter-intuitive observation that while GCN periodicity is pronounced in mRNA of genes with high expression, its de novo artificial introduction into the ramp sequence reduces the translation efficiency. Adequacy of the contribution of GCN codons representation to the translation level of the model genes’ (SKN7 and HMT1 and their sequence-altered variants) mRNA is proved by the scrupulous control experiments aimed at the transcription efficiency and protein stability measurements as well as the normalized translation efficiency scoring. The authors put forward a theory that translation levels inversely correlate with ramp GCN periodicity, confirming it not only with their model experiments on a pair of yeast genes, but also with the analysis of large-scale data previously published by other groups studying the role of the ramp region in translation efficiency. Finally, the authors propose a mechanistic model for the interaction of ribosome with mRNA (CAR-mRNA), which explains the regulatory principle of GCN periodicity (metaphorically described as the accelerator and braking system for ribosome translation).

It was a pleasure for me to read this manuscript. In form and in content significance, it recalls the classic papers of the 60-70s on the discovery of the basic principles of molecular biology. It is surprising that such fundamental and seemingly self-explanatory aspect of gene expression will be included in the coursebooks only in the third decade of the 21st century.

Undoubtedly, the theory proposed by the authors requires further testing of its applicability on the larger gene cohorts and within the translation systems of different organisms. Also these results call for the structural studies of the CAR-mRNA interface. However, to my mind the need for further development of this topic does not detract from the contribution already made by Barr et al. team. I would strongly recommend this manuscript for publication as it is.

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Reviewer #1: Yes: Andreas Savelsbergh

Reviewer #2: No