Serine/arginine-rich splicing factor 1

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Protein SFRS1 PDB 1x4a.png
Available structures
PDBOrtholog search: PDBe RCSB
AliasesSRSF1, ASF, SF2, SF2p33, SFRS1, SRp30a, ASF/SF2, serine/arginine-rich splicing factor 1, serine and arginine rich splicing factor 1
External IDsOMIM: 600812 MGI: 98283 HomoloGene: 31411 GeneCards: SRSF1
RefSeq (mRNA)



RefSeq (protein)



Location (UCSC)Chr 17: 58 – 58.01 MbChr 11: 87.94 – 87.94 Mb
PubMed search[3][4]
View/Edit HumanView/Edit Mouse

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.[5] ASF/SF2 is an essential sequence specific splicing factor involved in pre-mRNA splicing.[6][7][8] SRSF1 is the gene that codes for ASF/SF2[9] and is found on chromosome 17. The resulting splicing factor is a protein of approximately 33 kDa.[10] ASF/SF2 is necessary for all splicing reactions to occur, and influences splice site selection in a concentration-dependent manner, resulting in alternative splicing.[7] In addition to being involved in the splicing process, ASF/SF2 also mediates post-splicing activities, such as mRNA nuclear export and translation.[11]


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.[12][13] These modules have different functions within general splicing factor function.[13]


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.[10] Subsequent lariat formation during the first chemical step of pre-mRNA splicing also requires ASF/SF2.[10] 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.[8] ASF/SF2 also associates with the U2 snRNP.[15] During the reaction, ASF/SF2 promotes the use of intron proximal sites and hinders the use of intron distal sites, affecting alternative splicing.[16][17] 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.[6] ASF/SF2 accomplishes this regulation through direct or indirect binding to exonic splicing enhancer (ESE) sequences.[16]


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.[11] ASF/SF2 interacts with the nuclear export protein TAP in a regulated manner, controlling the export of mature mRNA from the nucleus.[18] 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.[19] 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.[19]

Regulation through phosphorylation[edit]

ASF/SF2 has the ability to be phosphorylated at the serines in its RS domain by the SR specific protein kinase, SRPK1.[13] SRPK1 and ASF/SF2 form an unusually stable complex of apparent Kd of 50nM.[12][18] 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.[13] This multi-phosphorylation directs ASF/SF2 to the nucleus, influencing a number of protein-protein interactions associated with splicing.[13] 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,[13] while phosphorylation directs ASF/SF2 to nuclear speckles.[18] 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.[20] In addition, hypophosphorylation and hyperphosphorylation of ASF/SF2 by Clk/Sty can lead to inhibition of splicing.[13]

Biological importance[edit]

Stability and fidelity[edit]

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.[8] In this way, ASF/SF2 is protecting cells from the potential deleterious effects of transcription itself.[8] ASF/SF2 is also implicated in cellular mechanisms to hinder exon skipping and to ensure splicing is occurring accurately and correctly.[10]

Development and growth[edit]

ASF/SF2 has been shown to have a critical function in heart development,[12] embryogenesis, tissue formation, cell motility, and cell viability in general.[21][22]

Clinical significance[edit]

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.[13] 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.[23] As such, ASF/SF2 is an important target for cancer therapy, as it is over-expressed in many tumors.[13]

Modifications and defects in the alternative splicing pathway are associated with a variety of human diseases.[24]

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.[25] ASF/SF2 action in the replication of HIV-1 is a potential target for HIV therapy.[25] 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.[26][27]


ASF/SF2 has been shown to interact with:


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  20. ^ Cao W, Jamison SF, Garcia-Blanco MA (Dec 1997). "Both phosphorylation and dephosphorylation of ASF/SF2 are required for pre-mRNA splicing in vitro". RNA. 3 (12): 1456–67. PMC 1369586. PMID 9404896.
  21. ^ Ghigna C, Giordano S, Shen H, Benvenuto F, Castiglioni F, Comoglio PM, Green MR, Riva S, Biamonti G (Dec 2005). "Cell motility is controlled by SF2/ASF through alternative splicing of the Ron protooncogene". Molecular Cell. 20 (6): 881–90. doi:10.1016/j.molcel.2005.10.026. PMID 16364913.
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  25. ^ a b Tange TØ, Kjems J (Sep 2001). "SF2/ASF binds to a splicing enhancer in the third HIV-1 tat exon and stimulates U2AF binding independently of the RS domain". Journal of Molecular Biology. 312 (4): 649–62. doi:10.1006/jmbi.2001.4971. PMID 11575921.
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  32. ^ a b Zhang WJ, Wu JY (Oct 1996). "Functional properties of p54, a novel SR protein active in constitutive and alternative splicing". Molecular and Cellular Biology. 16 (10): 5400–8. doi:10.1128/MCB.16.10.5400. PMC 231539. PMID 8816452.
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  36. ^ Labourier E, Rossi F, Gallouzi IE, Allemand E, Divita G, Tazi J (Jun 1998). "Interaction between the N-terminal domain of human DNA topoisomerase I and the arginine-serine domain of its substrate determines phosphorylation of SF2/ASF splicing factor". Nucleic Acids Research. 26 (12): 2955–62. doi:10.1093/nar/26.12.2955. PMC 147637. PMID 9611241.
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  38. ^ a b Xiao SH, Manley JL (Nov 1998). "Phosphorylation-dephosphorylation differentially affects activities of splicing factor ASF/SF2". The EMBO Journal. 17 (21): 6359–67. doi:10.1093/emboj/17.21.6359. PMC 1170960. PMID 9799243.
  39. ^ Cao W, Garcia-Blanco MA (Aug 1998). "A serine/arginine-rich domain in the human U1 70k protein is necessary and sufficient for ASF/SF2 binding". The Journal of Biological Chemistry. 273 (32): 20629–35. doi:10.1074/jbc.273.32.20629. PMID 9685421.

External links[edit]

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