Karmakar, Shilpita;
Ramirez, Oscar;
Paul, Kiran V;
Gupta, Abhishek K;
Kumari, Vandana;
Botti, Valentina;
de los Mozos, Igor Ruiz;
Neuenkirchen, Nils;
Ross, Robert J;
Karanicolas, John;
Neugebauer, Karla M;
Pillai, Manoj M
Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)
Sie können Bookmarks mittels Listen verwalten, loggen Sie sich dafür bitte in Ihr SLUB Benutzerkonto ein.
Medientyp:
E-Artikel
Titel:
Integrative genome-wide analysis reveals EIF3A as a key downstream regulator of translational repressor protein Musashi 2 (MSI2)
Beteiligte:
Karmakar, Shilpita;
Ramirez, Oscar;
Paul, Kiran V;
Gupta, Abhishek K;
Kumari, Vandana;
Botti, Valentina;
de los Mozos, Igor Ruiz;
Neuenkirchen, Nils;
Ross, Robert J;
Karanicolas, John;
Neugebauer, Karla M;
Pillai, Manoj M
Erschienen:
Oxford University Press (OUP), 2022
Erschienen in:NAR Cancer
Sprache:
Englisch
DOI:
10.1093/narcan/zcac015
ISSN:
2632-8674
Entstehung:
Anmerkungen:
Beschreibung:
<jats:title>Abstract</jats:title>
<jats:p>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.</jats:p>