Stem cell function and stress response are controlled by protein synthesis.
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.
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Sandra
S
Blanco
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Roberto
R
Bandiera
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Martyna
M
Popis
Department of Biology &Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Shobbir
S
Hussain
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Patrick
P
Lombard
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Jelena
J
Aleksic
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Abdulrahim
A
Sajini
University of Cambridge, CR-UK, Cambridge Institute, Li Ka Shing Centre, Robinson Way, Cambridge CB2 0RE, UK.
Hinal
H
Tanna
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Rosana
R
Cortés-Garrido
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Nikoletta
N
Gkatza
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Sabine
S
Dietmann
Wellcome Trust-Medical Research Council Cambridge Stem Cell Institute, Department of Genetics, University of Cambridge, Tennis Court Road, Cambridge CB2 1QR, UK.
Michaela
M
Frye
D000818:Animals; D002454:Cell Differentiation; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D003596:Cytosine / Q000378:metabolism; D005260:Female; D005472:Fluorouracil / Q000494:pharmacology; D018859:Hair Follicle / Q000166:cytology / Q000378:metabolism; D006801:Humans; D008297:Male; D008745:Methylation; D008780:Methyltransferases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051379:Mice; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology; D014176:Protein Biosynthesis; D012343:RNA, Transfer / Q000235:genetics / Q000378:metabolism; D012038:Regeneration; D012878:Skin Neoplasms / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000166:cytology / Q000502:physiology*; D013312:Stress, Physiological / Q000235:genetics
D003596:Cytosine; D012343:RNA, Transfer; D008780:Methyltransferases; C513146:Misu protein, mouse; C515610:NSUN2 protein, human; D005472:Fluorouracil