Protein Degradation with New Chemical Modalities
Chapter 13: Targeting Translation Regulation for the Development of Novel Drugs
Published:07 Oct 2020
I. Alroy, W. Mansour, and Y. Sheinberger, in Protein Degradation with New Chemical Modalities, ed. H. Weinmann and C. Crews, The Royal Society of Chemistry, 2020, ch. 13, pp. 254-276.
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Regulation of protein translation is not restricted to global coordination, but it is also highly specific as it is an important infliction point in the regulation of gene expression, because it offers a rapid and protein-selective response to environmental cues. For example, mRNA can be transported and stored in specific cellular compartments and rapidly produced in response to a signal. Indeed, selective and specific regulation of protein translation occurs at several levels: (1) mRNA is bound by proteins immediately at transcription, enabling mRNA processing, modification (epitranscriptomics), transport, cytoplasmic localization and availability for translation; (2) proteins regulate RNA-binding proteins occupancy on target mRNAs, thereby regulating mRNA half-life and translation initiation; (3) regulation of ribosome recruitment and processivity (i.e., rate of translation). This complex regulatory machinery offers multiple targets for therapeutic intervention in protein aggregation diseases and in targeting proteins which are considered hard targets, such as structural proteins, transcription factors and scaffold and assembly proteins. We have developed a method which visualizes specific or global protein translation inside mammalian cells by monitoring the activity of ribosomes. This uniquely enables the discovery of small molecules which specifically regulate translation and leads to the identification of novel targets for therapeutic intervention.