Alternatively Spliced Genes
127
Splicing Regulatory Elements
Specifc sequences in introns or exons that are recognized by trans-acting Factors to
allow either enhancement or repression oF splicing.
Splicing Regulators
Trans-acting Factors that interact with splicing regulatory elements to either stimulate
or inhibit splicing.
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An important step oF eukaryotic gene expression is pre-mRNA splicing, the process
oF removing intervening sequences (introns) From the nascent transcript (messenger
RNA precursor, or pre-mRNA). The discovery oF split genes in the viral genome and
subsequent research in the feld oF pre-mRNA splicing have greatly advanced our
understanding oF mammalian gene regulation. Studies on pre-mRNA splicing have
also Facilitated sequence analyses oF the human genome. With the completion oF
human genome sequencing, it is now Further appreciated that pre-mRNA splicing
and alternative splicing play critical roles in regulating gene expression and in
enhancing genetic diversity.
Evolutionarily, the basic machinery For pre-mRNA splicing appears to be highly
conserved among diFFerent species oF metazoans. In
Saccharomyces cerevisiae
,
although only a small percentage oF genes undergo splicing, more than 100 genes
have been identifed that are either dedicated to or involved in pre-mRNA splicing. In
mammals, pre-mRNA splicing is a crucial step For gene expression because the vast
majority oF mammalian transcription units contain one or more introns that must
be accurately removed to Form mature and Functional messenger RNA (mRNA)
species. In this chapter, we review the current knowledge about mammalian pre-
mRNA splicing, with special emphasis on the aspects related to the pathogenesis or
treatment oF human diseases.
1
Pre-mRNA Splicing and Splicing Machinery
1.1
Splicing Machinery: Spliceosome
Pre-mRNA
splicing
is
the
frst
step
oF
the
major
post-transcriptional
pro-
cesses
in
eukaryotic
gene
expression
(±ig. 1).
The
biochemical
reactions
oF
pre-mRNA splicing occur in a macro-
molecular
machine
named
the
spliceo-
some
. This large RNA–protein complex
contains, in addition to the pre-mRNA
substrate, several uridine-rich small nu-
clear ribonucleoprotein (UsnRNP) parti-
cles as well as a myriad oF non-snRNP
protein Factors. The splicing machinery is
similar in complexity and size to that oF
the protein synthesis machinery, the ribo-
some. In all cases studied so Far, splicing
reactions take place in the mature spliceo-
some inside the nucleus.
±or processing the majority oF introns
(the major class, also called the U2-type
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