Eukaryotic translation

Eukaryotic translation is the biological process by which messenger RNA is translated into proteins in eukaryotes. It consists of four phases: initiation, elongation, termination, and recapping. Initiation Translation initiation is the process by which the ribosome and its associated factors bind to an mRNA and are assembled at the start codon. This process is defined as either cap-dependent, in which the ribosome binds initially at the 5' cap and then travels to the stop codon, or as cap-independent, where the ribosome does not initially bind the 5' cap. Cap-dependent initiation Initiation of translation usually involves the interaction of certain key proteins, the initiation factors, with a special tag bound to the 5'-end of an mRNA molecule, the 5' cap, as well as with the 5' UTR. These proteins bind the small (40S) ribosomal subunit and hold the mRNA in place. eIF3 is associated with the 40S ribosomal subunit and plays a role in keeping the large (60S) riboso

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Ribosomes (ˈraɪbəˌsoʊm,_-boʊ-) are macromolecular machines, found within all cells, that perform biological protein synthesis (mRNA translation). Ribosomes link amino acids together in the order sp

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NRF2 Activation Confers Resistance to eIF4A Inhibitors in Cancer Therapy

Linlin Cao

Inhibition of the eIF4A RNA helicase with silvestrol and related compounds is emerging as a powerful anti-cancer strategy. We find that a synthetic silvestrol analogue (CR-1-31 B) has nanomolar activity across many cancer cell lines. It is especially active against aggressive MYC+/BCL2+ B cell lymphomas and this likely reflects the eIF4A-dependent translation of both MYC and BCL2. We performed a genome-wide CRISPR/Cas9 screen and identified mechanisms of resistance to this new class of therapeutics. We identify three negative NRF2 regulators (KEAP1, CUL3, CAND1) whose inactivation is sufficient to cause CR1-31-B resistance. NRF2 is known to alter the oxidation state of translation factors and cause a broad increase in protein production. We find that NRF2 activation particularly increases the translation of some eIF4A-dependent mRNAs and restores MYC and BCL2 production. We know that NRF2 functions depend on removal of sugar adducts by the frutosamine-3-kinase (FN3K). Accordingly, loss of FN3K results in NRF2 hyper-glycation and inactivation and resensitizes cancer cells to eIF4A inhibition. Together, our findings implicate NRF2 in the translation of eIF4A-dependent mRNAs and point to FN3K inhibition as a new strategy to block NRF2 functions in cancer.

2021

Ribo-DT: An automated pipeline for inferring codon dwell times from ribosome profiling data

Cédric Gobet, Felix Naef

Protein synthesis is an energy consuming process characterised as a pivotal and highly regulated step in gene expression. The net protein output is dictated by a combination of translation initiation, elongation and termination rates that have remained difficult to measure. Recently, the development of ribosome profiling has enabled the inference of translation parameters through modelling, as this method informs on the ribosome position along the mRNA. Here, we present an automated, reproducible and portable computational pipeline to infer relative single-codon and codon-pair dwell times as well as gene flux from raw ribosome profiling sequencing data. As a case study, we applied our workflow to a publicly available yeast ribosome profiling dataset consisting of 57 independent gene knockouts related to RNA and tRNA modifications. We uncovered the effects of those modifications on translation elongation and codon selection during decoding. In particular, knocking out mod5 and trm7 increases codon-specific dwell times which indicates their potential tRNA targets, and highlights effects of nucleotide modifications on ribosome decoding rate.

ACADEMIC PRESS INC ELSEVIER SCIENCE2022

Targeting cap-dependent translation blocks converging survival signals by AKT and PIM kinases in lymphoma

Elisa Oricchio

New anticancer drugs that target oncogenic signaling molecules have greatly improved the treatment of certain cancers. However, resistance to targeted therapeutics is a major clinical problem and the redundancy of oncogenic signaling pathways provides back-up mechanisms that allow cancer cells to escape. For example, the AKT and PIM kinases produce parallel oncogenic signals and share many molecular targets, including activators of cap-dependent translation. Here, we show that PIM kinase expression can affect the clinical outcome of lymphoma chemotherapy. We observe the same in animal lymphoma models. Whereas chemoresistance caused by AKT is readily reversed with rapamycin, PIM-mediated resistance is refractory to mTORC1 inhibition. However, both PIM- and AKT-expressing lymphomas depend on cap-dependent translation, and genetic or pharmacological blockade of the translation initiation complex is highly effective against these tumors. The therapeutic effect of blocking cap-dependent translation is mediated, at least in part, by decreased production of short-lived oncoproteins including c-MYC, Cyclin D1, MCL1, and the PIM1/2 kinases themselves. Hence, targeting the convergence of oncogenic survival signals on translation initiation is an effective alternative to combinations of kinase inhibitors.

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MicroRNA (miRNA) are small, single-stranded, non-coding RNA molecules containing 21 to 23 nucleotides. Found in plants, animals and some viruses, miRNAs are involved in RNA silencing and post-transc