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The RNAissance family: SR proteins as multifaceted regulators of gene expression

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Serine and arginine‐rich (SR) proteins play multiple roles in the eukaryotic gene expression pathway. Initially described as constitutive and alternative splicing factors, now it is clear that SR proteins are key determinants of exon identity and function as molecular adaptors, linking the pre‐messenger RNA (pre‐mRNA) to the splicing machinery. In addition, now SR proteins are implicated in many aspects of mRNA and noncoding RNA (ncRNA) processing well beyond splicing. These unexpected roles, including RNA transcription, export, translation, and decay, may prove to be the rule rather than the exception. To simply define, this family of RNA‐binding proteins as splicing factors belies the broader roles of SR proteins in post‐transcriptional gene expression. WIREs RNA 2015, 6:93–110. doi: 10.1002/wrna.1260 This article is categorized under: RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications RNA Processing > Splicing Mechanisms RNA Processing > Splicing Regulation/Alternative Splicing
Serine and arginine‐rich (SR) proteins regulate spliceosome assembly. Spliceosome assembly onto the pre‐messenger RNA (pre‐mRNA) occurs in a coordinated, stepwise manner. In E complex, SR proteins regulate U1 snRNP recruitment to the 5′ splice site GU, and U2AF35/65 bound to the pyrimidine tract and 3′ splice site AG. In the A complex, SR proteins may facilitate U2 snRNP binding at the branchpoint by neutralizing the negative phosphodiester backbone charge. SR proteins can also recruit U4/U6·U5 tri‐snRNP during B complex. Molecular rearrangements and dephosphorylation of SR proteins occur to form the catalytically active C complex, in which U2 and U6 interact, and U6 replaces U1 snRNP, and U5 coordinates exons prior to splicing and ligation. SF1, splicing factor 1; snRNP, small nuclear ribonucleoprotein; SR, SR protein; RS, arginine/serine motif; 5′ and 3′ splice sites are indicated by GU and AG dinucleotides, respectively; (Y)n, polypyrimidine tract; P, phosphate moiety].
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Serine and arginine‐rich (SR) proteins function in translation initiation. (a) SRSF1 bound to exported mRNAs can associate with mechanistic target of rapamycin (mTOR) kinase and recruit it to cytoplasmic mRNP complexes. This facilitates phosphorylation of 4E‐BP, causing dissociation from eIF4E and increasing the efficiency of cap‐dependent translation initiation. (b) SR proteins have also been shown to enhance cap‐independent translation initiation of viral RNAs that contain internal ribosome entry site (IRES) elements and constitutive transport elements (CTEs).
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The life cycle of a serine and arginine‐rich (SR) protein. (a) SR proteins remain localized to nuclear speckles until they are phosphorylated by Clk/Sty. At this point they can be recruited to areas of active transcription, possibly in Pol II‐dependent manner. (b) SR proteins can then bind to splicing enhancers in the nascent pre‐messenger RNA (pre‐mRNA) transcript to facilitate spliceosome assembly co‐transcriptionally in phosphorylation‐dependent manner. (c) Following maturation of the mRNA transcript, SR proteins, along with other factors (e.g., EJC proteins), can facilitate TAP binding to the mRNP and subsequent nuclear export. (d) After export, SR proteins can enhance the pioneering round of mRNA translation and send the transcript down one of two pathways: (e) the ribosome encounters no pretermination codons (PTCs) and continues with steady‐state translation or (f) a PTC is encountered and nonsense‐mediated decay proceeds. (g) Released SR proteins can then be phosphorylated by cytoplasmic SRPK, which triggers binding of transportin‐SRs and nuclear import of SR proteins for storage or further rounds of splicing. (h) SR proteins may also play roles in miRNA biogenesis by facilitating export of pre‐microRNAs to the cytoplasm for further processing and use in RNA‐induced silencing (i). SR, SR protein; P, phosphate moiety; TF, transcription factor; Pol II, RNA polymerase II; hn, hnRNP proteins; U2, U5, U6, U snRNPs; PPase, protein phosphatase; EJC, exon junction complex; PABP, poly‐A binding protein; TAP, TAP/nuclear export factor 1; Exo, exosome; SRPK, SR protein kinase; Trans‐SR, transportin‐SR; Expo5, exportin 5; AGO2, argonaute 2.
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Serine and arginine‐rich (SR) proteins regulate alternative splicing. (a) SR proteins have been shown to promote or inhibit U1/U2 small nuclear ribonucleoprotein (snRNP) recruitment with respect to their orientation to 5′ and 3′ splice sites. (b) SR proteins bound to adjacent exons can compete for U2 snRNP recruitment to their respective 3′ splice sites, likely depending on the ‘strength’ of the SR protein to recruit spliceosomal factors. (c) Phosphorylation states of the RS domain can influence SR protein‐dependent recruitment of U1 and U2 snRNPs. (d) Antagonistic relationships of SR proteins and hnRNP proteins often influence recruitment of spliceosomal factors. ESE/ESS, exonic splicing enhancers/exonic splicing silencers.
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RNA Processing > Splicing Regulation/Alternative Splicing
RNA Interactions with Proteins and Other Molecules > Protein–RNA Interactions: Functional Implications
RNA Interactions with Proteins and Other Molecules > Protein–RNA Recognition
RNA Processing > Splicing Mechanisms

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