In
molecular biology
Molecular biology is the branch of biology that seeks to understand the molecular basis of biological activity in and between cells, including biomolecular synthesis, modification, mechanisms, and interactions. The study of chemical and physi ...
, an exonic splicing enhancer (ESE) is a DNA
sequence motif
In biology, a sequence motif is a nucleotide or amino-acid sequence pattern that is widespread and usually assumed to be related to biological function of the macromolecule. For example, an ''N''-glycosylation site motif can be defined as ''As ...
consisting of 6 bases within an
exon
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequen ...
that directs, or enhances, accurate
splicing of heterogeneous nuclear RNA (
hnRNA
A primary transcript is the single-stranded ribonucleic acid ( RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs ...
) or
pre-mRNA
A primary transcript is the single-stranded ribonucleic acid (RNA) product synthesized by transcription of DNA, and processed to yield various mature RNA products such as mRNAs, tRNAs, and rRNAs. The primary transcripts designated to be mRNAs a ...
into messenger RNA (
mRNA
In molecular biology, messenger ribonucleic acid (mRNA) is a single-stranded molecule of RNA that corresponds to the genetic sequence of a gene, and is read by a ribosome in the process of Protein biosynthesis, synthesizing a protein.
mRNA is ...
).
Introduction
Short sequences of DNA are transcribed to
RNA
Ribonucleic acid (RNA) is a polymeric molecule essential in various biological roles in coding, decoding, regulation and expression of genes. RNA and deoxyribonucleic acid ( DNA) are nucleic acids. Along with lipids, proteins, and carbohydra ...
; then this RNA is translated to a
protein
Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residues. Proteins perform a vast array of functions within organisms, including catalysing metabolic reactions, DNA replication, respo ...
. A gene located in DNA will contain
introns
An intron is any nucleotide sequence within a gene that is not expressed or operative in the final RNA product. The word ''intron'' is derived from the term ''intragenic region'', i.e. a region inside a gene."The notion of the cistron .e., gene. ...
and
exons
An exon is any part of a gene that will form a part of the final mature RNA produced by that gene after introns have been removed by RNA splicing. The term ''exon'' refers to both the DNA sequence within a gene and to the corresponding sequence ...
. Part of the process of preparing the RNA includes
splicing out the introns, sections of RNA that do not code for the protein. The presence of exonic splicing enhancers is essential for proper identification of splice sites by the cellular machinery.
Role in splicing
SR protein
SR proteins are a conserved family of proteins involved in RNA splicing. SR proteins are named because they contain a protein domain with long repeats of serine and arginine amino acid residues, whose standard abbreviations are "S" and "R" respe ...
s bind to and promote exon splicing in regions with ESEs, while
heterogeneous ribonucleoprotein particle Heterogeneous nuclear ribonucleoproteins (hnRNPs) are complexes of RNA and protein present in the cell nucleus during transcription (genetics), gene transcription and subsequent post-transcriptional modification of the newly synthesized RNA (pre-mRN ...
s (hnRNPs) bind to and block exon splicing in regions with
exonic splicing silencer An exonic splicing silencer (ESS) is a short region (usually 4-18 nucleotides) of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing ...
s. Both types of proteins are involved in the assembly and proper functioning of
spliceosome
A spliceosome is a large ribonucleoprotein (RNP) complex found primarily within the nucleus of eukaryotic cells. The spliceosome is assembled from small nuclear RNAs (snRNA) and numerous proteins. Small nuclear RNA (snRNA) molecules bind to specifi ...
s.
During
RNA splicing
RNA splicing is a process in molecular biology where a newly-made precursor messenger RNA (pre-mRNA) transcript is transformed into a mature messenger RNA (mRNA). It works by removing all the introns (non-coding regions of RNA) and ''splicing'' b ...
,
U2 small nuclear RNA auxiliary factor 1
Splicing factor U2AF 35 kDa subunit is a protein that in humans is encoded by the ''U2AF1'' gene.
Function
This gene belongs to the splicing factor SR family of genes . U2AF1 is a subunit of the U2 Auxiliary Factor complex alongside a larger ...
(U2AF35) and
U2AF2
Splicing factor U2AF 65 kDa subunit is a protein that in humans is encoded by the ''U2AF2'' gene.
Function
In eukaryotes, the introns in the transcribed pre-mRNA first have to be removed by spliceosome in order to form a mature mRNA. A spliceo ...
(U2AF65) interact with the branch site and the 3' splice site of the intron to form the lariat. It is thought that SR proteins that bind to ESEs promote exon splicing by increasing interactions with U2AF35 and U2AF65.
Mutation of exonic splicing enhancer motifs is a significant contributor to genetic disorders and some cancers. Simple point mutations in ESEs can inhibit affinity for splicing factors and alter
alternative splicing
Alternative splicing, or alternative RNA splicing, or differential splicing, is an alternative splicing process during gene expression that allows a single gene to code for multiple proteins. In this process, particular exons of a gene may be ...
, leading to altered mRNA sequence and protein translation. A field of genetic research is dedicated to determining the location and significance of ESE motifs
in vivo
Studies that are ''in vivo'' (Latin for "within the living"; often not italicized in English) are those in which the effects of various biological entities are tested on whole, living organisms or cells, usually animals, including humans, and ...
.
Research
Computational methods were used to identify 238 candidate ESEs.
ESEs are clinically significant because synonymous point mutations previously thought to be
silent mutations
Silent mutations are mutations in DNA that do not have an observable effect on the organism's phenotype. They are a specific type of neutral mutation. The phrase ''silent mutation'' is often used interchangeably with the phrase '' synonymous mutat ...
located in an ESEs can lead to exon skipping and the production of a non functioning protein.
Disruption of an exon splicing enhancer in exon 3 of
MLH1
DNA mismatch repair protein Mlh1 or MutL protein homolog 1 is a protein that in humans is encoded by the MLH1 gene located on chromosome 3. It is a gene commonly associated with hereditary nonpolyposis colorectal cancer. Orthologs of human MLH1 h ...
gene is the cause of
HNPCC
Hereditary nonpolyposis colorectal cancer (HNPCC) or Lynch syndrome is an autosomal dominant genetic condition that is associated with a high risk of colon cancer as well as other cancers including endometrial cancer (second most common), ovary, ...
(hereditary nonpolyposis colorectal cancer) in a Quebec family.
There is evidence that these 236 hexamers that signal splicing are evolutionarily conserved.
See also
*
Exonic splicing silencer An exonic splicing silencer (ESS) is a short region (usually 4-18 nucleotides) of an exon and is a cis-regulatory element. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing ...
(ESS)
References
{{reflist
External links
ESE finder
Genetics