Article | Published:

Stem cell function and stress response are controlled by protein synthesis

Nature volume 534, pages 335340 (16 June 2016) | Download Citation

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.

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Accessions

Primary accessions

Gene Expression Omnibus

Data deposits

Mouse next-generation sequencing data have been deposited in the Gene Expression Omnibus under accession number GSE72067. Human data have been deposited in dbGAP under accession number phs000645.v2.p1.

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Acknowledgements

We thank J. Marioni and D. Odom for their advice on analysing the sequencing data. This work was funded by Cancer Research UK, Worldwide Cancer Research, the Medical Research Council (MRC), the European Research Council, and EMBO. Research in M.F.’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.

Author information

Affiliations

  1. Wellcome Trust—Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK

    • Sandra Blanco
    • , Roberto Bandiera
    • , Martyna Popis
    • , Patrick Lombard
    • , Jelena Aleksic
    • , Abdulrahim Sajini
    • , Rosana Cortés-Garrido
    • , Nikoletta Gkatza
    • , Sabine Dietmann
    •  & Michaela Frye
  2. Department of Biology & Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK

    • Shobbir Hussain
  3. University of Cambridge, CR-UK, Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK

    • Hinal Tanna

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Contributions

M.F., S.B. and R.B. designed experiments and performed data analysis. S.B., R.B., M.P., S.H., A.S., H.T., R.C.-G. and N.G. performed experiments. P.L., J.A. and S.D. performed bioinformatics analysis. M.F., S.B. and R.B. wrote the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Michaela Frye.

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https://doi.org/10.1038/nature18282

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