The exon-junction complex helicase eIF4A3 controls cell fate via coordinated regulation of ribosome biogenesis and translational output

Dimitris C. Kanellis, Jaime A. Espinoza, Asimina Zisi, Elpidoforos Sakkas, Jirina Bartkova, Anna Maria Katsori, Johan Boström, Lars Dyrskjøt, Helle Broholm, Mikael Altun, Simon J. Elsässer, Mikael S. Lindström*, Jiri Bartek

*Corresponding author af dette arbejde
40 Citationer (Scopus)

Abstract

Eukaryotic initiation factor 4A-III (eIF4A3), a core helicase component of the exon junction complex, is essential for splicing, mRNA trafficking, and nonsense-mediated decay processes emerging as targets in cancer therapy. Here, we unravel eIF4A3’s tumor-promoting function by demonstrating its role in ribosome biogenesis (RiBi) and p53 (de)regulation. Mechanistically, eIF4A3 resides in nucleoli within the small subunit processome and regulates rRNA processing via R-loop clearance. EIF4A3 depletion induces cell cycle arrest through impaired RiBi checkpoint–mediated p53 induction and reprogrammed translation of cell cycle regulators. Multilevel omics analysis following eIF4A3 depletion pinpoints pathways of cell death regulation and translation of alternative mouse double minute homolog 2 (MDM2) transcript isoforms that control p53. EIF4A3 expression and subnuclear localization among clinical cancer specimens correlate with the RiBi status rendering eIF4A3 an exploitable vulnerability in high-RiBi tumors. We propose a concept of eIF4A3’s unexpected role in RiBi, with implications for cancer pathogenesis and treatment.

OriginalsprogEngelsk
Artikelnummereabf7561
TidsskriftScience Advances
Vol/bind7
Udgave nummer32
Sider (fra-til)eabf7561
DOI
StatusUdgivet - aug. 2021

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