Editing Alternative splicing (section)

====Exon definition: Fas receptor====
[[File:Fas alternative splicing.jpg|thumb|right|Alternative splicing of the Fas receptor pre-mRNA]]
Multiple isoforms of the [[Fas receptor]] protein are produced by alternative splicing. Two normally occurring isoforms in humans are produced by an exon-skipping mechanism. An mRNA including exon 6 encodes the membrane-bound form of the Fas receptor, which promotes [[apoptosis]], or programmed cell death. Increased expression of Fas receptor in skin cells chronically exposed to the sun, and absence of expression in skin cancer cells, suggests that this mechanism may be important in elimination of pre-cancerous cells in humans.<ref name=Filipowicz>{{cite journal | vauthors = Filipowicz E, Adegboyega P, Sanchez RL, Gatalica Z | title = Expression of CD95 (Fas) in sun-exposed human skin and cutaneous carcinomas | journal = Cancer | volume = 94 | issue = 3 | pages = 814–9 | date = February 2002 | pmid = 11857317 | doi = 10.1002/cncr.10277 | s2cid = 23772719 | doi-access = free }}</ref> If exon 6 is skipped, the resulting mRNA encodes a soluble Fas protein that does not promote apoptosis. The inclusion or skipping of the exon depends on two antagonistic proteins, [[TIA1|TIA-1]] and polypyrimidine tract-binding protein (PTB).
* The 5' donor site in the intron downstream from exon 6 in the pre-mRNA has a weak agreement with the consensus sequence, and is not bound usually by the U1 snRNP. If U1 does not bind, the exon is skipped (see "a" in accompanying figure).
* Binding of TIA-1 protein to an intronic splicing enhancer site stabilizes binding of the U1 snRNP.<ref name=Matlin/> The resulting 5' donor site complex assists in binding of the splicing factor U2AF to the 3' splice site upstream of the exon, through a mechanism that is not yet known (see b).<ref name=Izquierdo2005>{{cite journal | vauthors = Izquierdo JM, Majós N, Bonnal S, Martínez C, Castelo R, Guigó R, Bilbao D, Valcárcel J | display-authors = 6 | title = Regulation of Fas alternative splicing by antagonistic effects of TIA-1 and PTB on exon definition | journal = Molecular Cell | volume = 19 | issue = 4 | pages = 475–84 | date = August 2005 | pmid = 16109372 | doi = 10.1016/j.molcel.2005.06.015 | doi-access = free }}
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* Exon 6 contains a pyrimidine-rich exonic splicing silencer, ''ure6'', where PTB can bind. If PTB binds, it inhibits the effect of the 5' donor complex on the binding of U2AF to the acceptor site, resulting in exon skipping (see c).

This mechanism is an example of exon definition in splicing. A spliceosome assembles on an intron, and the snRNP subunits fold the RNA so that the 5' and 3' ends of the intron are joined. However, recently studied examples such as this one show that there are also interactions between the ends of the exon. In this particular case, these exon definition interactions are necessary to allow the binding of core splicing factors prior to assembly of the spliceosomes on the two flanking introns.<ref name=Izquierdo2005/>