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Specificity of translational control during unfolded protein response

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Protein translation provides clues in the fight against disease

Many diseases are caused by defects in the process of mRNA translation or in the components of the translational machinery. A European study showed a new role for the structure of mRNAs in the regulation of translation with potential extrapolation to human disease.

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Gene expression is a complex process that involves many steps of regulation. RNA-binding proteins (RBPs) play a pivotal role in the recognition and subsequent translation of mRNA molecules by forming ribonucleoprotein complexes (RNPs) and coordinating all of the regulatory stages that RNA molecules pass through.

Innovative methodology to study RNA

To shed light into the process of translation, scientists of the EU-funded TRANSLATE project investigated protein-RNA and RNA-RNA interactions that take place inside cells. To identify protein-RNA associations at high resolution, they developed new techniques that integrate biochemistry and computational biology and were based on methodology developed during the preceding ERC-funded project CLIP. “The idea was to comprehend how cells respond to specific types of signals by regulating translation, and thus gene expression,″ explains project coordinator, Dr Jernej Ule. The generated methods rely on the iCLIP method which uses UV crosslinking and immunoprecipitation to purify short RNA fragments bound to a specific protein, and then identify these fragments by sequencing. Researchers developed a new method, called hybrid iCLIP (hiCLIP), to study how the secondary structure of RNAs defines the composition and function of RNPs. This led to the discovery of ‘long-range’ duplexes that connect regions that are surprisingly far apart within the same mRNA molecule. According to Ule, this “provided an unforeseen view of the complex structural conformations of human mRNAs, which might lead to an origami-like process of RNA compaction.″ These RNA duplexes are bound by Staufen 1 and 2, proteins that recognise double-stranded RNA primarily in the 3’ untranslated region (3’UTR) of mRNAs, where they can be involved in controlling mRNA stability, translation and localisation in cells.

Potential impact of RNA-RNA interactions

Researchers studied how cells modify RNA duplexes and RNA-RNA interactions in response to cellular signals to control translation of mRNAs into new proteins. This provided insight into the fundamental mechanisms underlying translational regulation, and its importance for rapid remodelling of gene expression in response to stress. The iCLIP and hiCLIP methods will serve as the foundation for the discovery of many more protein-RNA and RNA-RNA interactions with important roles in biology. Future plans include investigations of the roles that mRNA structure and the bound RNPs play in development and disease. “Our next steps will be to study the dynamics of protein-RNA complexes in development, and how mutations RNA-binding proteins disrupt the assembly and function of these complexes,″ envisages Dr Ule. This will be the topic of the upcoming ERC Advanced grant RNPdynamics. Considering that many human diseases are associated with defects in mRNA translation, the mechanisms uncovered by TRANSLATE are likely implicated in some of these diseases. Furthermore, mutations causing cancer or neurodegenerative diseases such as amyotrophic lateral sclerosis (ALS) often occur in RBPs, underscoring the clinical significance of the findings of the TRANSLATE study.

Keywords

TRANSLATE, protein, translation, mRNA, RNA-binding proteins (RBPs), sequence, iCLIP, hiCLIP, ribonucleoprotein complexes (RNPs), amyotrophic lateral sclerosis, cancer

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