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Stem cell function and stress response are controlled by protein synthesis.

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Blanco, Sandra 
Bandiera, Roberto 
Popis, Martyna 
Hussain, Shobbir 
Lombard, Patrick 


Whether protein synthesis and cellular stress response pathways interact to control stem cell function is currently unknown. Here we show that mouse skin stem cells synthesize less protein than their immediate progenitors in vivo, even when forced to proliferate. Our analyses reveal that activation of stress response pathways drives both a global reduction of protein synthesis and altered translational programmes that together promote stem cell functions and tumorigenesis. Mechanistically, we show that inhibition of post-transcriptional cytosine-5 methylation locks tumour-initiating cells in this distinct translational inhibition programme. Paradoxically, this inhibition renders stem cells hypersensitive to cytotoxic stress, as tumour regeneration after treatment with 5-fluorouracil is blocked. Thus, stem cells must revoke translation inhibition pathways to regenerate a tissue or tumour.



Animals, Cell Differentiation, Cell Proliferation, Cell Transformation, Neoplastic, Cytosine, Female, Fluorouracil, Hair Follicle, Humans, Male, Methylation, Methyltransferases, Mice, Neoplastic Stem Cells, Protein Biosynthesis, RNA, Transfer, Regeneration, Skin Neoplasms, Stem Cells, Stress, Physiological

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Springer Science and Business Media LLC
Medical Research Council (G0801904)
Cancer Research Uk (None)
Medical Research Council (MR/M01939X/1)
Worldwide Cancer Research (None)
British Skin Foundation (5010)
Cancer Research Uk (None)
European Research Council (310360)
Cancer Research Uk (None)
Medical Research Council (MC_PC_12009)
This work was funded by Cancer Research UK (CR-UK), Worldwide Cancer Research, the Medical Research Council (MRC), the European Research Council (ERC), and EMBO. Research in Michaela Frye's laboratory is supported by a core support grant from the Wellcome Trust and MRC to the Wellcome Trust-Medical Research Cambridge Stem Cell Institute.