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Lecture 20

BIOC 4403 Lecture Notes - Lecture 20: Spliceosome, Neural Development, Cd44

Biochem & Molecular Biology
Course Code
BIOC 4403
Archibald John

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1. types of
1. Exon skipping.
2. Alternative exon size.
3. lntron retention.
4. Less frequent:
- mutuaally exclusive exons;
- alternative promoter usage;
- alternative polyadenylation.
2. 1. Exon
whole exons are either skipped (i.e. left out) or
spliced into mRNA. Most common form of
splicing in metazoans.
3. 2
exon size
exons can also come in different sizes through
using different splice sites to be spliced into the
mRNA-this makes exons either shorter or longer
at either end. Second most common form of
splicing in metazoans.
4. 3 lntron
within genomic DNA and in unspliced pre-
mRNA exons are separated from each other by
introns, and splicing usually joins the exons
together. However, whole introns can
sometimes be retained in mRNAs ( i.e. remain
unspliced ). Most common form of splicing in
yeast and plants, but rarer in metazoans.
5. Transition
A. Mutations that leads to suboptimal
recognition of the exon and result in exon
B. Formation of a hairpin between two Alu
elements in opppsite orientation before an exon
can interrupt exon recognition, resulting
6. Mutations
that leads
to exon
Aa. Mutations can lead to a new alternative 5
splice site (5′ SS) or 3′ SS.
Ab. Mutations can lead to suboptimal
recognition of the 5′ SS.
Ac. Mutations in exons (or introns) can disrupt
an exonic splicing enhancer (ESE) (or intronic
splicing enhancer (ISE)) or may create an exonic
splicing silencer (ESS) (or intronic silencing
silencer (ISS)).
7. Four
categories of
altered gene
function by
A. Mutations affecting splice sites, the
polypyrimidine tract, the branch point, or
splicing enhancers lead to exon skipping or
intron retention.
B. Mutations in enhancer or silencer elements
can change the ratio of isoforms containing
alternative exons.
C. Mutations within introns can lead to
inclusion of intronic sequences (indicated by
red dashed rectangles) by creating a splice
site/pseudoexon (indicated by arrow) and/or
by creating an enhancer element (indicated
by asterisk), allowing recognition of a cryptic
splice site.
D. Insertion of transposable elements in the 3′
UTR of the fukutin gene leads to the alternate
use of splice sites producing a protein with a
different carboxy-terminal sequence.
8. Effects of AS
on the cellular
fate of the
encoded by an
spliced gene
A. Change between cytosol and nucleus,
typically by altering a nuclear localization
signal (NLS).
B. Change between plasma membrane and
cytosol, typically by changing a
transmembrane region (TM).
C. Change between nucleus and membrane
associated forms.
D. Generation of soluble, secreted forms,
typically by changing a transmembrane
region (TM).
E. Localization between different internal
F. Localization in the mitochondria, typically
by regulating a mitochondrial-targeting signal
9. Examples of
AS function
1. splicing repression via changes in the
cellular splicing code: the ribosomal protein
RPL30 regulates its own splicing.
2. A signalling cascade changes the splicing
pattern of the CD44 v5 exon.
3. AS appears to be an important factor in the
evolution of the nervous system in
vertebrates. Many complex AS events occur
specifically in neural development - Many AS
patterns are unique to humans.
4403 - 20 Alternative Splicing II
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