An exonic splicing silencer (ESS) is a short region (usually 4-18 nucleotides) of 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 ...

and is a

cis-regulatory element ''Cis''-regulatory elements (CREs) or ''Cis''-regulatory modules (CRMs) are regions of non-coding DNA which regulate the transcription of neighboring genes. CREs are vital components of genetic regulatory networks, which in turn control morphoge ...

. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions. ESSs inhibit or silence splicing of the

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 ...

and contribute to constitutive and

alternate 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 in ...

. To elicit the silencing affect, ESSs recruit proteins that will negatively affect the core splicing machinery.

Mechanism of action

Exonic splicing silencers work by inhibiting the splicing of pre-mRNA strands or promoting exon skipping. The single stranded pre-mRNA molecules need to have their

intronic 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 exonic regions spliced in order to be translated. ESSs silence splice sites adjacent to them by interfering with the components of the core splicing complex, such as the snRNP's, U1 and U2. This causes proteins that negatively influence splicing to be recruited to the splicing machinery. ESSs have four general roles: * inhibiting exon inclusion * inhibiting intron retention * regulating alternative 5' splice site usage * regulating alternative 3' splice site usage

Role in genetic diseases

Myotonic dystrophy Myotonic dystrophy (DM) is a type of muscular dystrophy, a group of genetic disorders that cause progressive muscle loss and weakness. In DM, muscles are often unable to relax after contraction. Other manifestations may include cataracts, intel ...

Myotonic dystrophy (MD) is most noticeably caused by inheriting an unstable CTG triplet expansion in the DMPK gene. In healthy genotypes two isoforms of an insulin receptor mRNA transcript exist. The isoform IR-A lacks exon 11 and is expressed ubiquitously in cells. Isoform IR-B contains exon 11 and is expressed in cells of the liver, muscles, kidney, and adipocytes. In individuals with MD, IR-A is

upregulated In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proce ...

in high amounts in skeletal muscle leading to the disease phenotype. The ESS nucleotide sequence exists within intron 10 and is thought to be dependent on the CUG triplet repeat in order to silence the splicing of exon 11. Silencing exon 11 splicing leads to the increased transcription of the IR-A isoform.

Cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

Mutations in the

CFTR Cystic fibrosis transmembrane conductance regulator (CFTR) is a membrane protein and anion channel in vertebrates that is encoded by the ''CFTR'' gene. Geneticist Lap-Chee Tsui and his team identified the CFTR gene in 1989 as the gene linked wit ...

gene are responsible for causing

cystic fibrosis Cystic fibrosis (CF) is a rare genetic disorder that affects mostly the lungs, but also the pancreas, liver, kidneys, and intestine. Long-term issues include difficulty breathing and coughing up mucus as a result of frequent lung infections. O ...

. A particular mutation occurs in the CFTR pre-mRNA and leads to the exclusion of exon 9, mRNA lacking this exon folds a truncated protein (a protein shortened by a mutation). Exclusion of exon 9 is mediated by a polymorphic locus with variable TG repeats and stretches of T nucleotides – this is abbreviated as (TG)mT(n). This locus is an exonic splicing silencer and is located upstream of the exon 9 splice site (site 3c). The silencing is related to the high number of TG repeats and decreased stretches of T repeats (T tracts). A combination of both these factors is shown to increase levels of exon skipping. The

TDP-43 TAR DNA-binding protein 43 (TDP-43, transactive response DNA binding protein 43 kDa) is a protein that in humans is encoded by the ''TARDBP'' gene. Structure TDP-43 is 414 amino acid residues long. It consists of 4 domains: an N-terminal d ...

protein is responsible for physically silencing the exon splicing site once it is recruited by the exonic splicing silencer (TG)mT(n). TDP-43 is a DNA binding protein and repressor, it binds to the TG repeat to cause exon 9 skipping. The role of the T tracts is not well understood.

Spinal muscular atrophy Spinal muscular atrophy (SMA) is a rare neuromuscular disorder that results in the loss of motor neurons and progressive muscle wasting. It is usually diagnosed in infancy or early childhood and if left untreated it is the most common genetic ...

Spinal muscular atrophy is caused by the

homozygous Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism. Mo ...

loss of the

SMN1 Survival of motor neuron 1 (''SMN1''), also known as component of gems 1 or ''GEMIN1'', is a gene that encodes the SMN protein in humans. Gene ''SMN1'' is the telomeric copy of the gene encoding the SMN protein; the centromeric copy is terme ...

gene. Humans have two isoforms of the SMN (survival motor neuron) gene, SMN1 and

SMN2 Survival of motor neuron 2 (''SMN2'') is a gene that encodes the SMN protein (full and truncated) in humans. Gene The ''SMN2'' gene is part of a 500 kb inverted duplication on chromosome 5q13. This duplicated region contains at least four ge ...

. The SMN1 gene produces a complete transcript, while SMN2 produces a transcript without exon 7 which results in a truncated protein. The ESS that contributes to the disease phenotype is the UAGACA nucleotide sequence. This sequence arises when a C-to-T mutation occurs at position +6 in exon 7 of the SMN2 gene. This transition point mutation leads to the exclusion of exon 7 from the mRNA transcript, it is also the only difference between the SMN2 and SMN1 gene. The UAGACA ESS is thought to work by disrupting an

exonic splicing enhancer In molecular biology, an exonic splicing enhancer (ESE) is a DNA sequence motif consisting of 6 bases within an exon that directs, or enhances, accurate splicing of heterogeneous nuclear RNA (hnRNA) or pre-mRNA into messenger RNA (mRNA). Introdu ...

and attracting proteins that inhibit splicing by binding sequences on exon 7.

Ataxia telangiecstasia

Mutations in the ATM gene are responsible for Ataxia telangiecstasia. These mutations are generally single base pair substitutions, deletions, or micro-insertions. A 4-nucleotide deletion within intron 20 of the ATM gene disrupts an exonic splicing silencer and causes the inclusion of a 65-nucleotide cryptic exon in the mature transcript. The inclusion of the cryptic exon results in protein truncation and atypical splicing patterns.

References

{{reflist Genetics