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Revealing molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome.


ABSTRACT: The major cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), an ancient protein required for translation of all eukaryotic genomes, is a surprising yet potent oncogenic driver. The genetic interactions that maintain the oncogenic activity of this key translation factor remain unknown. In this study, we carry out a genome-wide CRISPRi screen wherein we identify more than 600 genetic interactions that sustain eIF4E oncogenic activity. Our data show that eIF4E controls the translation of Tfeb, a key executer of the autophagy response. This autophagy survival response is triggered by mitochondrial proteotoxic stress, which allows cancer cell survival. Our screen also reveals a functional interaction between eIF4E and a single anti-apoptotic factor, Bcl-xL, in tumor growth. Furthermore, we show that eIF4E and the exon-junction complex (EJC), which is involved in many steps of RNA metabolism, interact to control the migratory properties of cancer cells. Overall, we uncover several cancer-specific vulnerabilities that provide further resolution of the cancer translatome.

SUBMITTER: Kuzuoglu-Ozturk D 

PROVIDER: S-EPMC8323864 | biostudies-literature | 2021 Jun

REPOSITORIES: biostudies-literature

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Revealing molecular pathways for cancer cell fitness through a genetic screen of the cancer translatome.

Kuzuoglu-Ozturk Duygu D   Hu Zhiqiang Z   Rama Martina M   Devericks Emily E   Weiss Jacob J   Chiang Gary G GG   Worland Stephen T ST   Brenner Steven E SE   Goodarzi Hani H   Gilbert Luke A LA   Ruggero Davide D  

Cell reports 20210601 13


The major cap-binding protein eukaryotic translation initiation factor 4E (eIF4E), an ancient protein required for translation of all eukaryotic genomes, is a surprising yet potent oncogenic driver. The genetic interactions that maintain the oncogenic activity of this key translation factor remain unknown. In this study, we carry out a genome-wide CRISPRi screen wherein we identify more than 600 genetic interactions that sustain eIF4E oncogenic activity. Our data show that eIF4E controls the tra  ...[more]

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