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000281787 1001_ $$aRodschinka, Geraldine$$b0
000281787 245__ $$aComparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control.
000281787 260__ $$aLondon [u.a.]$$bNature Publishing Group$$c2025
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000281787 520__ $$aThe translation of mRNA into proteins in multicellular organisms needs to be carefully tuned to changing proteome demands in development and differentiation, while defects in translation often have a disproportionate impact in distinct cell types. Here we used inducible CRISPR interference screens to compare the essentiality of genes with functions in mRNA translation in human induced pluripotent stem cells (hiPS cells) and hiPS cell-derived neural and cardiac cells. We find that core components of the mRNA translation machinery are broadly essential but the consequences of perturbing translation-coupled quality control factors are cell type dependent. Human stem cells critically depend on pathways that detect and rescue slow or stalled ribosomes and on the E3 ligase ZNF598 to resolve a distinct type of ribosome collision at translation start sites on endogenous mRNAs with highly efficient initiation. Our findings underscore the importance of cell identity for deciphering the molecular mechanisms of translational control in metazoans.
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000281787 650_7 $$2NLM Chemicals$$aRNA, Messenger
000281787 650_2 $$2MeSH$$aHumans
000281787 650_2 $$2MeSH$$aRNA, Messenger: genetics
000281787 650_2 $$2MeSH$$aRNA, Messenger: metabolism
000281787 650_2 $$2MeSH$$aProtein Biosynthesis
000281787 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: metabolism
000281787 650_2 $$2MeSH$$aInduced Pluripotent Stem Cells: cytology
000281787 650_2 $$2MeSH$$aCRISPR-Cas Systems
000281787 650_2 $$2MeSH$$aRibosomes: metabolism
000281787 650_2 $$2MeSH$$aCell Differentiation
000281787 650_2 $$2MeSH$$aMyocytes, Cardiac: metabolism
000281787 650_2 $$2MeSH$$aMyocytes, Cardiac: cytology
000281787 7001_ $$aForcelloni, Sergio$$b1
000281787 7001_ $$aKühner, Felix M$$b2
000281787 7001_ $$aWani, Sascha$$b3
000281787 7001_ $$0P:(DE-2719)2812261$$aRiemenschneider, Henrick$$b4$$udzne
000281787 7001_ $$0P:(DE-2719)2231621$$aEdbauer, Dieter$$b5$$udzne
000281787 7001_ $$aBehrens, Andrew$$b6
000281787 7001_ $$00000-0001-8598-6021$$aNedialkova, Danny D$$b7
000281787 773__ $$0PERI:(DE-600)2131437-8$$a10.1038/s41594-025-01616-3$$gVol. 32, no. 10, p. 1932 - 1946$$n10$$p1932 - 1946$$tNature structural & molecular biology$$v32$$x1545-9993$$y2025
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