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An '''exonic splicing silencer''' (ESS) is a short region (usually 4-18 nucleotides)<ref name=":0">{{Cite journal|pmid = 16793546|title = Comparative Analysis Identifies Exonic Splicing Regulatory Sequences — The Complex Definition of Enhancers and Silencers|last = Goren|first = Amir|date = June 23, 2006|journal = Molecular Cell |last2 = Ram|first2 = Oren|last3 = Amit|first3 = Maayan|last4 = Keren|first4 = Hadas|last5 = Lev-Maor|first5 = Galit|last6 = Vig|first6 = Ida|last7 = Pupko|first7 = Tal|last8 = Ast|first8 = Gil|doi=10.1016/j.molcel.2006.05.008|volume=22|issue = 6|pages=769–81|doi-access = free}}</ref> of an [[exon]] and is a [[Cis-Regulatory element|cis-regulatory element]]. A set of 103 hexanucleotides known as FAS-hex3 has been shown to be abundant in ESS regions.<ref name=":3">{{Cite journal|title = General and Specific Functions of Exonic Splicing Silencers in Splicing Control|journal = Molecular Cell|date = 2006-07-07|issn = 1097-2765|pmc = 1839040|pmid = 16797197|pages = 61–70|volume = 23|issue = 1|doi = 10.1016/j.molcel.2006.05.018|first = Zefeng|last = Wang|first2 = Xinshu|last2 = Xiao|first3 = Eric|last3 = Van Nostrand|first4 = Christopher B.|last4 = Burge}}</ref> ESSs inhibit or silence splicing of the [[Precursor mRNA|pre-mRNA]] and contribute to constitutive and [[Alternative splicing|alternate splicing]]. To elicit the silencing effect, ESSs recruit proteins that will negatively affect the core splicing machinery.<ref name=":0" />

== 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]] 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|snRNP's]], [[U1 spliceosomal RNA|U1]] and [[U2 spliceosomal RNA|U2]].<ref name=":1">{{Cite journal|title = Alternative splicing and genetic diversity: silencers are more frequently modified by SNVs associated with alternative exon/intron borders|url= |journal = Nucleic Acids Research|date = 2011-07-01|issn = 0305-1048|pmc = 3130264|pmid = 21398627|pages = 4942–4948|volume = 39|issue = 12|doi = 10.1093/nar/gkr081|first = Jorge E. S. de|last = Souza|first2 = Rodrigo F.|last2 = Ramalho|first3 = Pedro A. F.|last3 = Galante|first4 = Diogo|last4 = Meyer|first5 = Sandro J. de|last5 = Souza}}</ref> This causes proteins that negatively influence splicing to be recruited to the splicing machinery.

ESSs have four general roles:<ref name=":3" />
* 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]] (MD) is most noticeably caused by inheriting an unstable [[Trinucleotide repeat expansion|CTG triplet expansion]] in the [[Myotonin-protein kinase|''DMPK'' gene]]. In healthy genotypes two isoforms of an insulin receptor mRNA transcript exist. The isoform ''[[Insulin receptor|IR-A]]'' lacks exon 11 and is expressed ubiquitously in cells. Isoform ''[[Insulin receptor|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 high amounts in skeletal muscle leading to the disease phenotype.<ref name=":4">{{Cite journal|title = Silencers regulate both constitutive and alternative splicing events in mammals|journal = Cellular and Molecular Life Sciences|date = 2005-05-18|issn = 1420-682X|pages = 1579–1604|volume = 62|issue = 14|doi = 10.1007/s00018-005-5030-6|pmid = 15905961|first = U.|last = Pozzoli|first2 = M.|last2 = Sironi|pmc = 11139151}}</ref>

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.<ref name=":4" />

=== Cystic fibrosis ===
Mutations in the ''[[Cystic fibrosis transmembrane conductance regulator|CFTR]]'' gene are responsible for causing [[cystic fibrosis]]. 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).<ref name=":4" />

Exclusion of exon 9 is mediated by a [[Locus (genetics)|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.<ref name=":4" />

The [[TARDBP|TDP-43]] 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.<ref name=":4" />

=== Spinal muscular atrophy ===
[[Spinal muscular atrophy]] is caused by the [[Zygosity|homozygous]] loss of the ''[[SMN1]]'' gene. Humans have two isoforms of the SMN (survival motor neuron) gene, ''SMN1'' and ''[[SMN2]]''. The ''SMN1'' gene produces a complete transcript, while ''SMN2'' produces a transcript without exon 7 which results in a truncated protein.<ref name=":4" />

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 (genetics)|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.<ref name=":4" />

The UAGACA ESS is thought to work by disrupting an [[exonic splicing enhancer]] and attracting proteins that inhibit splicing by binding sequences on exon 7.<ref name=":4" />

=== Ataxia telangiectasia ===
Mutations in the ''[[Ataxia telangiectasia mutated|ATM]]'' gene are responsible for [[ataxia telangiectasia]]. These mutations are generally single base pair [[Point mutation|substitutions]], [[Deletion (genetics)|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.<ref name=":4" />

== References ==
{{reflist}}

[[Category:Genetics]]

Exonic splicing silencer - История изменений

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ru>OAbot: Open access bot: pmc updated in citation with #oabot.