SR protein
SR proteins were discovered in the 1990s in Northern Ireland, Belfast in amphibian oocytes, and later in humans.
SR proteins are important in constitutive and alternative pre-mRNA splicing, mRNA export, genome stabilization, nonsense-mediated decay, and translation.
Once splicing is complete the SR protein may or may not remain attached to help shuttle the mRNA strand out of the nucleus.
Through the mTOR pathway and interactions with polyribosomes, SR proteins can increase translation of mRNA.
Ataxia telangiectasia, neurofibromatosis type 1, several cancers, HIV-1, and spinal muscular atrophy have all been linked to alternative splicing by SR proteins.
[2] This antibody allowed identification of four SR proteins (SRp20, SRp40, SRp55 and SRp75) and demonstrated their conservation among vertebrates and invertebrates.
The RRM domain mediates the RNA interactions of the SR proteins by binding to exon splicing enhancer sequences.
From NMR, the RRM domain of SRSF1, an SR protein, has a RNA binding fold structure.
[10][11][12] SR proteins are located in two different types of nuclear speckles, interchromatin granule clusters and perichromatin fibrils.
Perichromatin fibrils are areas of gene transcription and where SR proteins associate with RNA polymerase II for co-transcriptional splicing.
Most SR proteins that do not shuttle out of the nucleus with an RNA transcript have nuclear retention signals.
[9][11] SR proteins have been shown to have roles in alternative and constitutive splicing resulting in differential gene expression and also play a part in mRNA export, genome stabilization, non-sense mediated decay, and translation.
SR proteins and hnRNPs compete for binding to ESEs and ESSs sequences in exons.
[14][15] SR proteins may work in an antagonistic fashion, competing with each other to bind to exonic splicing enhancers.
Some evidence suggests that selection of the mRNA splicing variant depends upon the relative ratios of SR proteins.
Experiments have shown that knocking down SR proteins with RNAi shows no detectable phenotype in C. elegans.
[13][16] SR proteins select alternative upstream 3' splice sites by recruiting U2AF35 and U2AF65 to specific ESE pyrimidine sequences in the exon of the pre-mRNA transcript.
SR proteins might be able to bind directly to the 5' splice site and recruit the U1 complex of the spliceosome.
Thus the phosphorylation of the RS domain determines if the SR proteins stays with the RNA transcript after co-transcription splicing and while the mRNP matures.
The methylation and charge of arginine residues in the RRM domain also contributes to the export of SR proteins associated with mRNA.
[9][10][11] SR proteins can increase genome stability by preventing the formation of R loops in the DNA strand that is actively being transcribed during transcription.
SR protein SC35 has the ability to bind to the largest subunit of RNA polymerase II at the phosphorylated C-terminal domain.
[2] SR proteins can alternatively splice pre-mRNA transcripts to include nonsense-mediated decay (NMD) codons in the mRNA.
If a pre-mRNA transcript has a duplicated 5' splice site and SR proteins are over expressed then NMD can be upregulated.
For example, SC35 SR protein can alternatively splice a SC35 pre-mRNA to include a NMD codon in the mRNA.
High levels of SF2/ASF produce an isoform of MNK2 that increases cap-dependent translation by promoting phosphorylation of MAPK-independent eIF4E.
SF2/ASF can also interact with polyribosomes to directly influence translation of mRNA into protein by recruiting component of the mTOR pathway.
Mutations in pre-mRNA can affect the correct splice site selection for SR proteins.
[1] Mutations in mRNA, because of nonsense-associated altered splicing by SR proteins, have been linked to ataxia telangiectasia, neurofibromatosis type 1, several cancers, HIV-1, and spinal muscular atrophy.
New drug treatments for HIV infections are looking to target specific SR proteins to prevent the virus from replicating in cells.
