mRNA export and RNA processing in human disease (lect 3) Flashcards
What complexes are involved in mRNA export?
TREX complex
-associates with 5’ cap (ensuring mRNA has been processed)
-jumps to exon junction complex (ensuring splicing has happened)
-export can only happen when mRNA has been fully processed
Nxf1 complex
-binds to RNA and to FG repeats in nucleoporins (drives export)
How does mRNA export route depend on RNA length?
hnRNPC acts as a molecular ruler
-if RNA is too short (<200-300nts), it is exported by PHAX and CRM1
-if longer, hnRNPC wraps around 230-240nts and promotes recruitment of Nxf1 so is exported by mRNA export pathway
How are proteins recycled after mRNA export?
proteins have a nuclear localisation signal which allows them to be imported through the nuclear pore back into the nucleus without any bound RNA
Spinal muscular atrophy
splicing defect
mutation in SMN1
-normally have SMN1 and non-functional SMN2 (exon 7 skipped means SMN made can’t oligomerise), so without SMN1 can not translate any mRNA for SMN so no functional SMN made
Cure: using antisense oligomers to recognise introns, exon 7 included in SMN1 so functional SMN made
What does SMN do?
involved in snRNP biogenesis
-triggers assembly of SM protein ring in snRNP exported into cytoplasm
-snRNP can then be capped and imported back into nucleus where it finishes maturing in a Cajal body
Motor neurone disease
Lots of genes involved, many of which are RNA binding proteins
eg. Fus - regulates splicing, coupling it to transcription
-Fus binds U1, etc
-mislocation of Fus in cytoplasm means bound U1 is stuck in cytoplasm, rather than being in nucleus
How does the cell ensure mRNA has been fully processed before being exported?
TREX recruitment is dependent on processing
-once recruited to the cap binding complex, TREX jumps to the exon junction complex to reach internal regions of mRNA -> ensures capping and splicing has occurred (splicing ensured bc exon junction complex only bound when exons are next to eachother!)
