Proofreading and spellchecking: A two-tier strategy for pre-mRNA splicing quality control

Multi-tier strategies exist in many biochemical processes to ensure a maximal fidelity of the reactions. In this review, we focus on the two-tier quality control strategy that ensures the quality of the products of the pre-mRNA splicing reactions catalyzed by the spliceosome. The first step in the quality control process relies on kinetic proofreading mechanisms that are internal to the spliceosome and that are performed by ATP-dependent RNA helicases. The second quality control step, spellchecking, involves recognition of unspliced pre-mRNAs or aberrantly spliced mRNAs that have escaped the first proofreading mechanisms, and subsequent degradation of these molecules by degradative enzymes in the nucleus or in the cytoplasm. This two-tier quality control strategy highlights a need for high fidelity and a requirement for degradative activities that eliminate defective molecules. The presence of multiple quality control activities during splicing underscores the importance of this process in the expression of genetic information.