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

Kuzuoğlu-Öztürk, Duygu; Hu, Zhiqiang; Rama, Martina; Devericks, Emily; Weiss, Jacob; Chiang, Gary G.; Worland, Stephen T.; Brenner, Steven E.; Goodarzi, Hani; Gilbert, Luke A.; Ruggero, Davide

doi:10.1016/j.celrep.2021.109321

Cited by 10 publications

(7 citation statements)

References 66 publications

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“…Compounds targeting the translation elongation factor eEF1A, such as the synthetic ternatin variant dA3, have shown promise in preclinical experiments, and another eEF1A inhibitor, Plitidepsin, has been clinically approved for the treatment of multiple myeloma (Carelli et al, 2015;Keysar et al, 2020). Research supports the robust efficacy of combinational therapies of translation inhibitors with known therapeutic compounds, such as inhibitors of antiapoptotic proteins and targeted therapeutics (Anderson et al, 2016;Kuzuoglu-Ozturk et al, 2021;Thompson et al, 2021). Targeting translation from initiation through termination is an exciting new therapeutic avenue that may help overcome resistance to other anticancer agents, providing more effective treatments.…”

Section: Discussionmentioning

confidence: 99%

“…Although eIF4E has emerged as a high priority therapeutic target, the genetic interacting partners that act in concert with eIF4E‐dependent translational control to maintain cancer cell fitness are not well characterized. Our lab recently performed a genome‐wide CRISPRi screening to identify synthetic lethal partners of eIF4E, which uncovered more than 600 genetic interactions that sustain eIF4E oncogenic activity (Kuzuoglu‐Ozturk et al , 2021). Each interaction represents a potential target for combination therapy that can selectively target cancer cells at the post‐transcriptional level.…”

Section: Introductionmentioning

confidence: 99%

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Protein synthesis control in cancer: selectivity and therapeutic targeting

2022

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Translational control of mRNAs is a point of convergence for many oncogenic signals through which cancer cells tune protein expression in tumorigenesis. Cancer cells rely on translational control to appropriately adapt to limited resources while maintaining cell growth and survival, which creates a selective therapeutic window compared to non-transformed cells. In this review, we first discuss how cancer cells modulate the translational machinery to rapidly and selectively synthesize proteins in response to internal oncogenic demands and external factors in the tumor microenvironment. We highlight the clinical potential of compounds that target different translation factors as anti-cancer therapies. Next, we detail how RNA sequence and structural elements interface with the translational machinery and RNA-binding proteins to coordinate the translation of specific pro-survival and pro-growth programs. Finally, we provide an overview of the current and emerging technologies that can be used to illuminate the mechanisms of selective translational control in cancer cells as well as within the microenvironment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Protein synthesis control in cancer: selectivity and therapeutic targeting

2022

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“…Interestingly, a recent genome-wide CRISPRi screen identified exon junction complex (EJC) and spliceosome components as lethal partners of eIF4E. The list of identified genetic eIF4E partners also includes more than twenty genes coding for proteins involved in ribonucleoprotein complex biogenesis, including ribosome biogenesis and other nuclear functions [ 73 ]. These findings clearly highlight the functional proximity of eIF4E with the nuclear pathways of RNA maturation.…”

Section: Rna Maturation Nuclear Export and Translation Focusing On The Roles Of Cap-chaperonesmentioning

confidence: 99%

The Cap-Binding Complex CBC and the Eukaryotic Translation Factor eIF4E: Co-Conspirators in Cap-Dependent RNA Maturation and Translation

Mars

Ghram

Culjkovic-Kraljacic

et al. 2021

Cancers

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The translation of RNA into protein is a dynamic process which is heavily regulated during normal cell physiology and can be dysregulated in human malignancies. Its dysregulation can impact selected groups of RNAs, modifying protein levels independently of transcription. Integral to their suitability for translation, RNAs undergo a series of maturation steps including the addition of the m7G cap on the 5′ end of RNAs, splicing, as well as cleavage and polyadenylation (CPA). Importantly, each of these steps can be coopted to modify the transcript signal. Factors that bind the m7G cap escort these RNAs through different steps of maturation and thus govern the physical nature of the final transcript product presented to the translation machinery. Here, we describe these steps and how the major m7G cap-binding factors in mammalian cells, the cap binding complex (CBC) and the eukaryotic translation initiation factor eIF4E, are positioned to chaperone transcripts through RNA maturation, nuclear export, and translation in a transcript-specific manner. To conceptualize a framework for the flow and integration of this genetic information, we discuss RNA maturation models and how these integrate with translation. Finally, we discuss how these processes can be coopted by cancer cells and means to target these in malignancy.

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“…Upstream inputs to eEF2K are well described and include calcium ions, calmodulin, and anabolic signaling pathways such as mTORC1, mitogen-activated protein kinases (MAPKs), and adenosine monophosphate–activated protein kinase (AMPK) that regulate eEF2K activity ( 12 ). Disturbances in the translational control machinery are implicated in several human diseases including cancers ( 13 ) and many neurological disorders, including neurodegeneration and autism spectrum disorders (ASDs) ( 14 , 15 ).…”

Section: Introductionmentioning

confidence: 99%

The autism susceptibility kinase, TAOK2, phosphorylates eEF2 and modulates translation

Henis,

Rücker,

Scharrenberg

et al. 2024

Sci. Adv.

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Genes implicated in translation control have been associated with autism spectrum disorders (ASDs). However, some important genetic causes of autism, including the 16p11.2 microdeletion, bear no obvious connection to translation. Here, we use proteomics, genetics, and translation assays in cultured cells and mouse brain to reveal altered translation mediated by loss of the kinase TAOK2 in 16p11.2 deletion models. We show that TAOK2 associates with the translational machinery and functions as a translational brake by phosphorylating eukaryotic elongation factor 2 (eEF2). Previously, all signal-mediated regulation of translation elongation via eEF2 phosphorylation was believed to be mediated by a single kinase, eEF2K. However, we show that TAOK2 can directly phosphorylate eEF2 on the same regulatory site, but functions independently of eEF2K signaling. Collectively, our results reveal an eEF2K-independent signaling pathway for control of translation elongation and suggest altered translation as a molecular component in the etiology of some forms of ASD.

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

Cited by 10 publications

References 66 publications

Protein synthesis control in cancer: selectivity and therapeutic targeting

Protein synthesis control in cancer: selectivity and therapeutic targeting

The Cap-Binding Complex CBC and the Eukaryotic Translation Factor eIF4E: Co-Conspirators in Cap-Dependent RNA Maturation and Translation

The autism susceptibility kinase, TAOK2, phosphorylates eEF2 and modulates translation

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