Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control

The translation of mRNA into proteins in multicellular organisms needs to be carefully tuned to changing proteome demands in development and differentiation, and 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 (hiPSC) and hiPSC-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 highly 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 novel type of ribosome collisions 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.