Regulation of alternative splicing
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Explain how Sxl results in exon skipping.
Only in females, Sxl bind to the 3’ of an intron, blocking the association of U2AF and U2 snRNP to the branch-point A. This silences the splicing of the specific intron Sxl is bound to, thus resulting in exon skipping.
What is the cascade of regulated splicing that controls sex determination in Drosophila?
• Sxl leads to skipping of exon 4 • Tra leads to alternative 3’ splice site usage and leads to exclusion of exon 2 • In Dsx gne, Rbp1 and Tra2 are SR proteins that bind to ESE sites in the exon 4 of females. As a result, only exon 4 is included in females while excluded in males Dsx is a transcription factor that regulates expression of genes important in male and female development.
What are the three classes of mutations affecting RNA splicing?
• Mutations affecting cis-acting elements of a specific gene such as mutations in ESS, U1 binding site, etc. • Mutations in core splicing factors such as mutations affecting spliceosomal proteins such U4/U6/U5 tri-small nuclear ribonucleoprotein particles in retinitis pigmentosa. • Mutations in trans-acting factors (RNA binding proteins) that regulate splicing
What are therapies to modulate RNA mis-splicing?
• Small molecules have been developed that target splicing factors to modulate their activities. • Antisense oligos (ASOs) are designed to recognize specific RNA splicing regulatory elements.
Give a concrete example of disease caused by mis-splicing.
Retinitis pigmentosa is a progressive disease that is characterized by initial night blindness and loss of peripheral vision, followed by central retinal degeneration. Affected by mutations in U4/U6/U5 of spliceosome.
What is the mechanism of mutually exclusive exons?
When one exon is incorporated in the final product, the neighboring specific exons don’t get incorporated => mechanisms that regulate this * Steric interference => There is an overlap between U1 and U2 binding sites, thus preventing both to bind at the same time; this determines which exon is sliced * Spliceosomal incompatibility => Some introns have AU-AC sequences instead of GU-AG sequences, the specific snRNPs (U11/U12) used to splice these introns are not compatible with typical snRNPs * Nonsense mediated decay => Exons are regulated by combinations of splicing activators and repressors; RNA that contain exons that are not multiple of 3, nonsense mediated decay degrades them