What is Splicing

8/3/2019 What is Splicing

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What is RNA splicing?


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Genetic information is transferred from genes to theproteins theyencode via a messenger RNA

intermediate

DNA GENE

messenger RNA

(mRNA)

protein

transcription

translation


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The intron is also present in the RNA copy of the geneand must be removed by a process called RNA

splicing

protein

translation

mRNA

RNA splicing

pre-mRNAintron


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Splicing a pre-mRNA involves two reactions

pre-mRNA

intron branchpoint

A

spliced mRNA

Step 2

intermediates

Step 1

A


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RNA is produced in the nucleus of the cell. ThemRNA has to be transported to the cytoplasm toproduce proteins

Ribosomes are RNA-protein machines that makeproteins, translating the coding information in the

mRNA


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Pre-messenger RNA Processing

cytoplasm

nucleus

mRNA

RNA splicing

M7

G AAAAAAA200

pre-mRNAintronexon exon

AAAAAAA200M7G

transport

M7G AAAAAAA200

ribosomes

protein

cap poly(A) tail


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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 themRNA can be translated to produce protein


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However, multiple introns may be spliceddifferently 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 aresimilar but not identical and may havedistinct properties. This is

important in complex organisms

3 5421pre-mRNA


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Different signals in the pre-mRNA anddifferent proteins

cause spliceosomes to form in particular positions to givealternative splicing

We are studying how mRNAs and proteins interact inorder to understand how these machines work in generaland, in particular, how RNA splicing is regulated as itaffects which proteins are produced in each cell and

tissue in the body.


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765

75

65 7

Fas pre-mRNA

APOPTOSIS

Alternative splicing can generate mRNAs encoding proteins withdifferent, even opposite functions

(programmed

cell death)

Fas ligand

Soluble Fas

(membrane)

Fas

Fas ligand

(membrane-

associated)

(+)

(-)


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Alternative splicing can generate tens of thousands of mRNAsfrom a single primary transcript

12 48 33 2

Combinatorial selection of one exon at each of four variable regions generates more than38,000 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


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Examples of the potential consequences of mutations on splicing

3 541 2

A BCMutations occur

on the DNA(in a gene)

1 2

mutation Atruncated mRNA

541 2

mutation Bexon 3 skipped

3 541 2

mutation Clonger exon 4

3 541 2

no mutationnormal mRNA

normal protein

active

truncated protein

inactive

protein of different size (smaller or longer)

inactive or aberrant function


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Pathologies resulting from aberrant splicing can begrouped in two major categories

Mutations affecting proteins that are involved in splicingExamples: Spinal Muscular Atrophy

Retinitis Pigmentosa

Myotonic Dystrophy

Mutations affecting a specific messenger RNA and disturbing itsnormal splicing patternExamples: -Thalassemia

DuchenneMuscular DystrophyCystic FibrosisFrasier Syndrome

Frontotemporal Dementia and Parkinsonism


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Therefore, understanding the mechanism of RNAsplicing in normal cells and how it is regulated in

different tissues and at different stages ofdevelopment of an organism is essential in order todevelop strategies to correct aberrant splicing in

human pathologies

What is Splicing

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