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Rna splicing
RNA splicing is the process by which introns, or non-coding sequences, are removed from pre-messenger RNA (pre-mRNA) to produce mature mRNA that can be translated into protein. Most genes contain introns that are removed by a spliceosome, a complex of RNA and proteins, leaving just the coding exons to form mRNA. Alternative splicing allows one gene to encode multiple proteins by selecting different combinations of exons. Errors in splicing can cause diseases if they result in truncated or abnormal proteins.
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Rna splicing
- 1. What is RNAsplicing?
- 2. Genetic information istransferred from genes to the proteins they encode via a “messenger” RNA intermediate DNA GENE messenger RNA (mRNA) protein transcription translation
- 3. Most genes havetheir protein-coding information interrupted by non-coding sequences called “introns”. The coding sequences are then called “exons” DNA GE NE intron exon 1 exon 2 transcription precursor-mRNA (pre-mRNA) intron
- 4. The intron isalso present in the RNA copy of the gene and must be removed by a process called “RNA splicing” protein translation mRNA RNA splicing pre-mRNA intron
- 5. Splicing a pre-mRNAinvolves two reactions pre-mRNA intron branchpoint A spliced mRNA Step 2 intermediates Step 1 A
- 6. Splicing occurs ina “spliceosome” an RNA-protein complex (simplified) pre-mRNA spliced mRNA spliceosome (~100 proteins + 5 small RNAs) Splicing works similarly in different organisms, for example in yeast, flies, worms, plants and animals.
- 7. RNA is producedin 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
- 8. Pre-messenger RNA Processing cytoplasm nucleus mRNA RNAsplicing M7 G AAAAAAA200 pre-mRNA intronexon exon AAAAAAA200 M7 G transport M7 G AAAAAAA200 ribosomes protein cap poly(A) tail
- 9. Alternative splicing In humans,many genes contain multiple introns 3 4 51 2 1 2 3 54 intron 2 intron 3 intron 4intron 1 Usually all introns must be removed before the mRNA can be translated to produce protein
- 10. However, multiple intronsmay be spliced differently in different circumstances, for example in different tissues. 1 2 3 5Heart muscle mRNA 1 43 5Uterine muscle mRNA 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 3 5421pre-mRNA
- 11. Different signals inthe 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.
- 12. 765 75 65 7 Fas pre-mRNA APOPTOSIS Alternativesplicing can generate mRNAs encoding proteins with different, even opposite functions (programmed cell death) Fas ligand Soluble Fas (membrane) Fas Fas ligand (membrane- associated) (+) (-)
- 13. Alternative splicing cangenerate tens of thousands of mRNAs from a single primary transcript 12 48 33 2 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 The protein variants are important for wiring of the nervous system and for immune response protein mRNA pre-mRNA
- 14. Examples of thepotential consequences of mutations on splicing 3 541 2 A B CMutations occur on the DNA (in a gene) 1 2 mutation A truncated mRNA 541 2 mutation B exon 3 skipped 3 541 2 mutation C longer exon 4 3 541 2 no mutation normal mRNA normal protein active truncated protein inactive protein of different size (smaller or longer) inactive or aberrant function
- 15. Pathologies resulting fromaberrant 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
- 16. Therefore, understanding themechanism 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