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What is RNA splicing? Genetic information is transferred from genes to the proteins they encode via a “messenger” RNA intermediate DNA GENE transcription messenger RNA (mRNA) translation protein Most genes have their protein-coding information interrupted by non-coding sequences called “introns”. The coding sequences are then called “exons” DNA exon 1 intron exon 2 GE NE transcription precursor-mRNA (pre-mRNA) intron The intron is also present in the RNA copy of the gene and must be removed by a process called “RNA splicing” pre-mRNA intron RNA splicing mRNA translation protein Splicing a pre-mRNA involves two reactions intron branchpoint pre-mRNA A Step 1 intermediates A Step 2 spliced mRNA Splicing occurs in a “spliceosome” an RNA-protein complex (simplified) spliceosome (~100 proteins + 5 small RNAs) pre-mRNA spliced mRNA Splicing works similarly in different organisms, for example in yeast, flies, worms, plants and animals. RNA is produced in the nucleus of the cell. The mRNA has to be transported to the cytoplasm to produce proteins Ribosomes are RNA-protein machines that make proteins, translating the coding information in the mRNA Pre-messenger RNA Processing pre-mRNA M7G exon intron exon AAAAAAA200 cap RNA splicing mRNA M7G nucleus AAAAAAA200 transport cytoplasm M7G AAAAAAA200 ribosomes protein poly(A) tail Alternative splicing In humans, many genes contain multiple introns intron 1 1 intron 3 intron 2 2 3 1 2 3 intron 4 4 4 5 Usually all introns must be removed before the mRNA can be translated to produce protein 5 However, multiple introns may be spliced differently in different circumstances, for example in different tissues. Heart muscle mRNA pre-mRNA 1 1 2 3 2 Uterine muscle mRNA 5 3 1 3 4 4 5 5 Thus one gene can encode more than one protein. The proteins are similar but not identical and may have distinct properties. This is important in complex organisms Different signals in the pre-mRNA and different proteins cause spliceosomes to form in particular positions to give alternative splicing We are studying how mRNAs and proteins interact in order to understand how these machines work in general and, in particular, how RNA splicing is regulated as it affects which proteins are produced in each cell and tissue in the body. Alternative splicing can generate mRNAs encoding proteins with different, even opposite functions Fas ligand Fas 5 6 7 (membraneassociated) Fas pre-mRNA 5 (+) 6 7 APOPTOSIS (programmed cell death) (-) Fas ligand 5 7 Soluble Fas (membrane) Alternative splicing can generate tens of thousands of mRNAs from a single primary transcript Combinatorial selection of one exon at each of four variable regions generates more than 38,000 different mRNAs and proteins in the Drosophila cell adhesion molecule Dscam 12 48 33 2 pre-mRNA mRNA protein The protein variants are important for wiring of the nervous system and for immune response Examples of the potential consequences of mutations on splicing A Mutations occur on the DNA (in a gene) 1 2 no mutation normal mRNA 1 2 3 4 normal protein active B 3 mutation A truncated mRNA 5 C 1 2 truncated protein inactive 4 5 mutation B exon 3 skipped 1 2 4 mutation C longer exon 4 5 1 2 3 4 protein of different size (smaller or longer) inactive or aberrant function 5 Pathologies resulting from aberrant splicing can be grouped in two major categories Mutations affecting proteins that are involved in splicing Examples: Spinal Muscular Atrophy Retinitis Pigmentosa Myotonic Dystrophy Mutations affecting a specific messenger RNA and disturbing its normal splicing pattern Examples: ß-Thalassemia Duchenne Muscular Dystrophy Cystic Fibrosis Frasier Syndrome Frontotemporal Dementia and Parkinsonism Therefore, understanding the mechanism of RNA splicing in normal cells and how it is regulated in different tissues and at different stages of development of an organism is essential in order to develop strategies to correct aberrant splicing in human pathologies