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Ribosome-associated mRNA quality control mechanisms ensure the fidelity of protein translation.sup.1,2. Although these mechanisms have been extensively studied in yeast, little is known about their role in mammalian tissues, despite emerging evidence that stem cell fate is controlled by translational mechanisms.sup.3,4. One evolutionarily conserved component of the quality control machinery, Dom34 (in higher eukaryotes known as Pelota (Pelo)), rescues stalled ribosomes.sup.5. Here we show that Pelo is required for mammalian epidermal homeostasis. Conditional deletion of Pelo in mouse epidermal stem cells that express Lrig1 results in hyperproliferation and abnormal differentiation of these cells. By contrast, deletion of Pelo in Lgr5-expressing stem cells has no effect and deletion in Lgr6-expressing stem cells induces only a mild phenotype. Loss of Pelo results in accumulation of short ribosome footprints and global upregulation of translation, rather than affecting the expression of specific genes. Translational inhibition by rapamycin-mediated downregulation of mTOR (mechanistic target of rapamycin kinase) rescues the epidermal phenotype. Our study reveals that the ribosome-rescue machinery is important for mammalian tissue homeostasis and that it has specific effects on different stem cell populations.Loss of the ribosome-rescue factor Pelo in a subset of mouse epidermal stem cells results in hyperproliferation and altered differentiation of these cells., Author(s): Kifayathullah Liakath-Ali [sup.1] [sup.8] , Eric W. Mills [sup.2] , Inês Sequeira [sup.1] , Beate M. Lichtenberger [sup.1] [sup.3] , Angela Oliveira Pisco [sup.1] , Kalle H. Sipilä [sup.1] [...]