Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2).

Autor:	Karmakar S; Section of Hematology, Yale Cancer Center, New Haven, CT 06511, USA., Ramirez O; Section of Hematology, Yale Cancer Center, New Haven, CT 06511, USA., Paul KV; Section of Hematology, Yale Cancer Center, New Haven, CT 06511, USA., Gupta AK; Section of Hematology, Yale Cancer Center, New Haven, CT 06511, USA., Kumari V; Section of Hematology, Yale Cancer Center, New Haven, CT 06511, USA., Botti V; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06510, USA., de Los Mozos IR; Institute of Neurology, University College London and The Francis Crick Institute, London NW1 1AT, UK., Neuenkirchen N; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA., Ross RJ; Department of Cell Biology, Yale University School of Medicine, New Haven, CT 06511, USA., Karanicolas J; Program in Molecular Therapeutics, Fox Chase Cancer Center, Philadelphia, PA 19111, USA., Neugebauer KM; Department of Molecular Biophysics and Biochemistry, Yale University School of Medicine, New Haven, CT 06510, USA., Pillai MM; Section of Hematology, Yale Cancer Center, New Haven, CT 06511, USA.
Jazyk:	angličtina
Zdroj:	NAR cancer [NAR Cancer] 2022 May 02; Vol. 4 (2), pp. zcac015. Date of Electronic Publication: 2022 May 02 (Print Publication: 2022).
DOI:	10.1093/narcan/zcac015
Abstrakt:	Musashi 2 (MSI2) is an RNA binding protein (RBP) that regulates asymmetric cell division and cell fate decisions in normal and cancer stem cells. MSI2 appears to repress translation by binding to 3' untranslated regions (3'UTRs) of mRNA, but the identity of functional targets remains unknown. Here, we used individual nucleotide resolution cross-linking and immunoprecipitation (iCLIP) to identify direct RNA binding partners of MSI2 and integrated these data with polysome profiling to obtain insights into MSI2 function. iCLIP revealed specific MSI2 binding to thousands of mRNAs largely in 3'UTRs, but translational differences were restricted to a small fraction of these transcripts, indicating that MSI2 regulation is not triggered by simple binding. Instead, the functional targets identified here were bound at higher density and contain more 'UAG' motifs compared to targets bound nonproductively. To further distinguish direct and indirect targets, MSI2 was acutely depleted. Surprisingly, only 50 transcripts were found to undergo translational induction on acute loss. Using complementary approaches, we determined eukaryotic translation initiation factor 3A (EIF3A) to be an immediate, direct target. We propose that MSI2 downregulation of EIF3A amplifies these effects on translation. Our results also underscore the challenges in defining functional targets of RBPs since mere binding does not imply a discernible functional interaction. (© The Author(s) 2022. Published by Oxford University Press on behalf of NAR Cancer.)
Databáze:	MEDLINE
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