Journal Article

DZNE-2025-01180

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Comparative CRISPRi screens reveal a human stem cell dependence on mRNA translation-coupled quality control.

Rodschinka, G. ; Forcelloni, S. ; Kühner, F. M. ; Wani, S. ; Riemenschneider, H.DZNE* ; Edbauer, D.DZNE* ; Behrens, A. ; Nedialkova, D. D.

2025
Nature Publishing Group London [u.a.]

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Please use a persistent id in citations: doi:10.1038/s41594-025-01616-3

Abstract: 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.

Keyword(s): Humans (MeSH) ; RNA, Messenger: genetics (MeSH) ; RNA, Messenger: metabolism (MeSH) ; Protein Biosynthesis (MeSH) ; Induced Pluripotent Stem Cells: metabolism (MeSH) ; Induced Pluripotent Stem Cells: cytology (MeSH) ; CRISPR-Cas Systems (MeSH) ; Ribosomes: metabolism (MeSH) ; Cell Differentiation (MeSH) ; Myocytes, Cardiac: metabolism (MeSH) ; Myocytes, Cardiac: cytology (MeSH) ; RNA, Messenger

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Contributing Institute(s):

1. Cell Biology of Neurodegeneration (AG Edbauer)

Research Program(s):

1. 352 - Disease Mechanisms (POF4-352) (POF4-352)

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Database coverage:
; BIOSIS Previews ; Biological Abstracts ; Clarivate Analytics Master Journal List ; Current Contents - Life Sciences ; DEAL Nature ; Ebsco Academic Search ; Essential Science Indicators ; IF >= 15 ; JCR ; Nationallizenz ; SCOPUS ; Science Citation Index Expanded ; Web of Science Core Collection

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