Nuclear RNA surveillance of genome expression: From yeast to mammals

In all organisms the genetic information is encoded in the sequence of DNA. To be used this information must be copied into a related polymer, RNA. Two major classes of RNA product are made. The stable RNAs play key functional roles in several metabolic pathways, including the protein synthesis. Messenger RNAs (mRNAs) carry the information that is used to specify the sequence, and therefore the structure, of the proteins. The mature functional forms of all RNAs are generated by complex pathways, which process the RNAs and assemble them into particles together with specific proteins. At all steps in gene expression, accuracy is of prime importance. However, high fidelity is energetically expensive and systems that are very accurate will always be slower and/or consume more energy than less accurate systems. Very frequently biological pathways combine a moderately accurate process with one or more proof reading steps that detect and either correct or degrade defective products. We hypothesise that RNA maturation pathways are continuously monitored by quality control systems, on which we will be focusing. We would like to understand how problems are detected, and how this leads to the destruction of the defective RNAs or RNA-protein complexes. The objective of this proposal is to elucidate the mechanisms governing nuclear RNA quality control. The many steps required for the production of fucntional RNAs have traditionally been studied as independent processes, and each of the participating groups is an expert in one (or a few) of these. To break new scientific ground pooling of expertises, tools and techniques from different fields and model organisms is needed - and this will be provided by the Nuclear RNA Surveillance network.

Eukaryotic RNAs are produced and matured in the cell nucleus. Major events in the biogenesis of most RNAs, including splicing, 3' end processing and RNP formation, occur co-transcriptionally, on at least some tanscripts. Coupling with transcription increases the efficiency and specificity of the processing-packaging systems and sets up an assembly line with 'built in' quality control where a RNP maturation step will only occur if the preceding reaction was successful. This is because enzymes and complexes harboring RNA degradative activity are immediately available to rapidly degrade the RNAs of aberrant, or sub-optimal RNP molecules. The objective of this proposal is to elucidate the mechanisms governing nuclear RNA surveillance. We will analyse the mechanism and significance of the recognition and degradation of aberrant RNAs by the exosome complex of 3' to 5' exonucleases and is cofactors, notably the Trf4/Air/Mtr4 polyadenylation complex (TRAMP4).