Stem cell function and stress response are controlled by protein synthesis

Sandra Blanco, Roberto Bandiera, Martyna Popis, Shobbir Hussain, Patrick Lombard, Jelena Aleksic, Abdulrahim Sajini, Hinal Tanna, Rosana Cortés-Garrido, Nikoletta Gkatza, Sabine Dietmann and Michaela Frye ()
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Sandra Blanco: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Roberto Bandiera: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Martyna Popis: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Shobbir Hussain: University of Bath
Patrick Lombard: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Jelena Aleksic: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Abdulrahim Sajini: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Hinal Tanna: University of Cambridge, CR-UK, Cambridge Institute, Li Ka Shing Centre
Rosana Cortés-Garrido: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Nikoletta Gkatza: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Sabine Dietmann: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge
Michaela Frye: Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, University of Cambridge

Nature, 2016, vol. 534, issue 7607, 335-340

Abstract: Abstract 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.

Date: 2016
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DOI: 10.1038/nature18282

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