TY  - JOUR
AU  - Rodschinka, Geraldine
AU  - Forcelloni, Sergio
AU  - Kühner, Felix M
AU  - Wani, Sascha
AU  - Riemenschneider, Henrick
AU  - Edbauer, Dieter
AU  - Behrens, Andrew
AU  - Nedialkova, Danny D
TI  - Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control.
JO  - Nature structural & molecular biology
VL  - 32
IS  - 10
SN  - 1545-9993
CY  - London [u.a.]
PB  - Nature Publishing Group
M1  - DZNE-2025-01180
SP  - 1932 - 1946
PY  - 2025
AB  - The 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.
KW  - Humans
KW  - RNA, Messenger: genetics
KW  - RNA, Messenger: metabolism
KW  - Protein Biosynthesis
KW  - Induced Pluripotent Stem Cells: metabolism
KW  - Induced Pluripotent Stem Cells: cytology
KW  - CRISPR-Cas Systems
KW  - Ribosomes: metabolism
KW  - Cell Differentiation
KW  - Myocytes, Cardiac: metabolism
KW  - Myocytes, Cardiac: cytology
KW  - RNA, Messenger (NLM Chemicals)
LB  - PUB:(DE-HGF)16
C6  - pmid:40646310
C2  - pmc:PMC12527931
DO  - DOI:10.1038/s41594-025-01616-3
UR  - https://pub.dzne.de/record/281787
ER  -