Serine/arginine-rich splicing factor 1

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Lua error in Module:Infobox_gene at line 53: attempt to index field 'wikibase' (a nil value). Serine/arginine-rich splicing factor 1 (SRSF1) also known as alternative splicing factor 1 (ASF1), pre-mRNA-splicing factor SF2 (SF2) or ASF1/SF2 is a protein that in humans is encoded by the SRSF1 gene.[1] ASF/SF2 is an essential sequence specific splicing factor involved in pre-mRNA splicing.[2][3][4] SRSF1 is the gene that codes for ASF/SF2[5] and is found on chromosome 17. The resulting splicing factor is a protein of approximately 33 kDa.[6] ASF/SF2 is necessary for all splicing reactions to occur, and influences splice site selection in a concentration-dependent manner, resulting in alternative splicing.[3] In addition to being involved in the splicing process, ASF/SF2 also mediates post-splicing activities, such as mRNA nuclear export and translation.[7]

Structure

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ASF/SF2 is an SR protein, and as such, contains two functional modules: an arginine-serine rich region (RS domain), where the bulk of ASF/SF2 regulation takes place, and two RNA recognition motifs (RRMs), through which ASF/SF2 interacts with RNA and other splicing factors.[8][9] These modules have different functions within general splicing factor function.[9]

Splicing

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ASF/SF2 is an integral part of numerous components of the splicing process. ASF/SF2 is required for 5’ splice site cleavage and selection, and is capable of discriminating between cryptic and authentic splice sites.[6] Subsequent lariat formation during the first chemical step of pre-mRNA splicing also requires ASF/SF2.[6] ASF/SF2 promotes recruitment of the U1 snRNP to the 5’ splice site, and bridges the 5’ and 3’ splice sites to facilitate splicing reactions.[4] ASF/SF2 also associates with the U2 snRNP.[11] During the reaction, ASF/SF2 promotes the use of intron proximal sites and hinders the use of intron distal sites, affecting alternative splicing.[12][13] Alternative splicing is affected by ASF/SF2 in a concentration-dependent manner; differing concentrations of ASF/SF2 is a mechanism for alternative splicing regulation, and will result in differing amounts of product isoforms.[2] ASF/SF2 accomplishes this regulation through direct or indirect binding to exonic splicing enhancer (ESE) sequences.[12]

Post-splicing

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ASF/SF2, in the presence of elF4E, promotes the initiation of translation of ribosome-bound mRNA by suppressing the activity of 4E-BP and recruiting molecules for further regulation of translation.[7] ASF/SF2 interacts with the nuclear export protein TAP in a regulated manner, controlling the export of mature mRNA from the nucleus.[14] An increase in cellular ASF/SF2 also will increase the efficiency of nonsense-mediated mRNA decay (NMD), favoring NMD that occurs before mRNA release from the nucleus over NMD that occurs after mRNA export from the nucleus to the cytoplasm.[15] This shift in NMD caused by increased ASF/SF2 is accompanied by overall enhancement of the pioneer round of translation, through elF4E-bound mRNA translation and subsequent translationally active ribosomes, increased association of pioneer translation initiation complexes with ASF/SF2, and increased levels of active TAP.[15]

Regulation through phosphorylation

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ASF/SF2 has the ability to be phosphorylated at the serines in its RS domain by the SR specific protein kinase, SRPK1.[9] SRPK1 and ASF/SF2 form an unusually stable complex of apparent Kd of 50nM.[8][14] SRPK1 selectively phosphorylates up to twelve serines in the RS domain of ASF/SF2 through a directional and processive mechanism, moving from the C terminus to the N terminus.[9] This multi-phosphorylation directs ASF/SF2 to the nucleus, influencing a number of protein-protein interactions associated with splicing.[9] ASF/SF2's function in export of mature mRNA from the nucleus is dependent on its phosphorylation state; dephosphorylation of ASF/SF2 facilitates binding to TAP,[9] while phosphorylation directs ASF/SF2 to nuclear speckles.[14] Both phosphorylation and dephosphorylation of ASF/SF2 are important and necessary for proper splicing to occur, as sequential phosphorylation and dephosphorylation marks the transitions between stages in the splicing process.[16] In addition, hypophosphorylation and hyperphosphorylation of ASF/SF2 by Clk/Sty can lead to inhibition of splicing.[9]

Biological importance

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Stability and fidelity

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ASF/SF2 is involved in genomic stability; it is thought that RNA Polymerase recruits ASF/SF2 to nascent RNA transcripts to impede formation of mutagenic DNA:RNA hybrid R-loop structures between the transcript and the template DNA.[4] In this way, ASF/SF2 is protecting cells from the potential deleterious effects of transcription itself.[4] ASF/SF2 is also implicated in cellular mechanisms to hinder exon skipping and to ensure splicing is occurring accurately and correctly.[6]

Development and growth

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ASF/SF2 has been shown to have a critical function in heart development,[8] embryogenesis, tissue formation, cell motility, and cell viability in general.[17][18]

Clinical significance

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SFRS1 is a proto-oncogene, and thus ASF/SF2 can act as an oncoprotein; it can alter the splicing patterns of crucial cell cycle regulatory genes and suppressor genes.[9] ASF/SF2 controls the splicing of various tumor suppressor genes, kinases, and kinase receptors, all of which have the potential to be alternatively spliced into oncogenic isoforms.[19] As such, ASF/SF2 is an important target for cancer therapy, as it is over-expressed in many tumors.[9]

Modifications and defects in the alternative splicing pathway are associated with a variety of human diseases.[20]

ASF/SF2 is involved in the replication of HIV-1, as HIV-1 needs a delicate balance of spliced and unspliced forms of its viral DNA.[21] ASF/SF2 action in the replication of HIV-1 is a potential target for HIV therapy.[21] ASF/SF2 is also implicated in the production of T cell receptors in Systemic Lupus Erythematosus, altering specific chain expression in T cell receptors through alternative splicing.[22][23]

Interactions

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ASF/SF2 has been shown to interact with:

References

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  • Overview of all the structural information available in the PDB for UniProt: Q07955 (Serine/arginine-rich splicing factor 1) at the PDBe-KB.
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