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  1. Evaluation Summary:

    In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in APC and KRAS. The authors identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and differentiation, suggesting that translation elongation can be used as tumour-specific target.

    (This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. Reviewer #1 agreed to share their name with the authors.)

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  2. Reviewer #1 (Public Review):

    The manuscript by Knight et al. show that the ribosomal protein RPL24 regulates protein synthesis and tumour proliferation, while reduced expression of RPL24 suppresses KRAS mutated colorectal cancer (CRC) via reduced translation elongation. The manuscript is well written and the experimental design is very thorough that combines a number of preclinical models and biochemical assays to demonstrate that Rpl24Bst slows down translation elongation and suppresses tumour growth via increased eEF2 phosphorylation. The conclusion is well supported by the experimental data presented, which implies that translation elongation can be a potential therapeutic target of KRAS mutated CRC. Importantly, Rpl24Bst in wildtype intestine does not affect epithelial cell proliferation and differentiation, suggesting that translation elongation can be used as tumour-specific target.

    Overall, the work is of high quality with impressive amount of work. However, it remains unclear why and how the tumour suppressive role of Rpl24Bst is specific to KRAS G12D mutation only, considering that increased eEF2 phosphorylation is also observed in the KRAS wildtype model.

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  3. Reviewer #2 (Public Review):

    In this study, Knight and colleagues investigate the role of the ribosome and translational control in colorectal tumours. A mutation of a protein of the large ribosomal subunit, RPL24, is used to suppress tumours driven by two mutations found commonly in cancer, in Apc and Kras. Knight et al identify a mechanistic output of the RPL24 BST mutation, eEF2 phosphorylation, which they demonstrate is a major effector in inhibiting tumour cell translation and proliferation. By targeting the eEF2 kinase eEF2K, they restore protein synthesis in RPL24 mutant cells. This work enhances the concept of targeting translational control in tumours.

    The strengths are the tumour assays including the genetic experiments which identify the role of eEF2 phosphorylation inhibiting tumour formation, including targeting the kinase, eEF2K. This places eEF2 phosphorylation as a critical node in translational control in tumours. This work is timely in identifying this pathway as a therapeutic target for further dissection. What is yet to be discovered is how RPL24-bst induces eEF2-phosphorylation. It is unclear how direct this mechanism is and whether it involves ribosome heterogeneity and/or translational stress.

    Overall a significant study identifying a novel target to explore in colorectal cancer.

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