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Gene Review

SRSF1  -  serine/arginine-rich splicing factor 1

Homo sapiens

Synonyms: ASF, ASF-1, Alternative-splicing factor 1, MGC5228, OK/SW-cl.3, ...
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Disease relevance of SFRS1

  • Furthermore, expression of high levels of SF2/ASF inhibits Rev function and impairs HIV replication in vivo [1].
  • We have shown previously that ASF/SF2 inhibits adenovirus IIIa pre-mRNA splicing by binding to an intronic repressor element [2].
  • Here, we show that the SR protein SF2/ASF is part of a complex that forms upon the 79-nucleotide negative regulatory element (NRE) that is thought to be pivotal in posttranscriptional regulation of late gene expression in human papillomavirus type 16 (HPV-16) [3].
  • Functional coexpression of serine protein kinase SRPK1 and its substrate ASF/SF2 in Escherichia coli [4].
  • Long-lasting protection, requiring only three immunizations, was achieved against a low-dose challenge with the SF2 strain of HIV-1 and a subsequent high-dose SF2 challenge administered 1 year later without an intervening boost [5].

High impact information on SFRS1


Chemical compound and disease context of SFRS1


Biological context of SFRS1

  • ASF/SF2 stimulates exon 6A splicing through specific interaction with the enhancer sequence [13].
  • We propose that in some cases the ratio of SF2/ASF to hnRNP A1 may play a role in regulating alternative splicing by exon inclusion or skipping through the antagonistic effects of these proteins on alternative splice site selection [14].
  • With appropriate alternative exons, an excess of SF2/ASF promotes exon inclusion, whereas an excess of hnRNP A1 causes exon skipping [14].
  • Deletion analysis mapped the phosphorylation sites to a region containing an (Arg-Ser)8 repeat beginning at residue 204, and far-Western analysis showed that the region is required for binding of SRPKs to SF2/ASF [15].
  • Moreover, cross-linking experiments show that both ASF/SF2 and SC35 are able to displace binding of hnRNP A1 to the G-rich element, suggesting that the binding sites for these proteins are overlapping [16].

Anatomical context of SFRS1


Associations of SFRS1 with chemical compounds

  • These and other results suggest a central role for ASF/SF2 in the function of purine-rich splicing enhancers [21].
  • A domain within this segment, which begins with Arg240 and ends with Asp270, was shown to bind specifically to the arginine/serine domain of ASF/SF2 using a yeast two-hybrid system and a far Western assay [22].
  • It has been clearly documented that the arginine/serine domain of ASF/SF2 is responsible for binding to the U1 70k protein [22].
  • Depletion of ASF/SF2 from the cells by tetracycline greatly decreased viral RNA expression and RNA splicing at the proximal 3' splice site while increasing use of the distal 3' splice site in the remaining viral RNAs [23].
  • We have screened for similar proteins in plants by using monoclonal antibodies specific for a phosphoserine epitope of the SR proteins (mAb1O4) or for SF2/ASF [24].

Physical interactions of SFRS1

  • Based upon a model of SRPK1 bound to a segment encompassing the docking motif and active-site peptide of ASF/SF2, we suggest a mechanism for processive phosphorylation and propose that the atypical resiliency we observed is critical for SRPK1's processive activity [25].

Co-localisations of SFRS1


Regulatory relationships of SFRS1

  • We found that an excess of SF2/ASF effectively prevents inappropriate exon skipping and also influences the selection of mutually exclusive tissue-specific exons in natural beta-tropomyosin pre-mRNA [14].
  • 5. SF2/ASF and SRp40 activate the ESE and are required for efficient 3' splice site usage and binding of the U1 snRNP to the downstream 5' splice site no [27].

Other interactions of SFRS1


Analytical, diagnostic and therapeutic context of SFRS1

  • Indirect immunofluorescence analysis revealed that endogenous hPRP4 was distributed in a nuclear speckled pattern and colocalized with SF2/ASF in HeLa S3 cells [31].
  • Analyses involving UV cross-linking and immunoprecipitation indicated that only four (SRp30a, SRp40, SRp55, and SRp75) of six essential splicing factors known as SR proteins bind to the active enhancer RNA [32].
  • RT-PCR analysis revealed a marked induction of SC35 and ASF/SF2 as well as mRNA levels in malignant ovarian tissue [33].
  • Molecular cloning, polymorphism and mapping of the porcine SFRS1 gene [34].
  • SF1, SF2, and SF4B appear to be required for cleavage of the pre-mRNA at the 5' splice site and lariat formation, whereas SF3 and SF4A are only required for cleavage at the 3' splice site and exon ligation [35].


  1. HIV Rev-dependent binding of SF2/ASF to the Rev response element: possible role in Rev-mediated inhibition of HIV RNA splicing. Powell, D.M., Amaral, M.C., Wu, J.Y., Maniatis, T., Greene, W.C. Proc. Natl. Acad. Sci. U.S.A. (1997) [Pubmed]
  2. Human splicing factor ASF/SF2 encodes for a repressor domain required for its inhibitory activity on pre-mRNA splicing. Dauksaite, V., Akusjärvi, G. J. Biol. Chem. (2002) [Pubmed]
  3. SF2/ASF binds the human papillomavirus type 16 late RNA control element and is regulated during differentiation of virus-infected epithelial cells. McPhillips, M.G., Veerapraditsin, T., Cumming, S.A., Karali, D., Milligan, S.G., Boner, W., Morgan, I.M., Graham, S.V. J. Virol. (2004) [Pubmed]
  4. Functional coexpression of serine protein kinase SRPK1 and its substrate ASF/SF2 in Escherichia coli. Yue, B.G., Ajuh, P., Akusjärvi, G., Lamond, A.I., Kreivi, J.P. Nucleic Acids Res. (2000) [Pubmed]
  5. Long-term protection of chimpanzees against high-dose HIV-1 challenge induced by immunization. Lubeck, M.D., Natuk, R., Myagkikh, M., Kalyan, N., Aldrich, K., Sinangil, F., Alipanah, S., Murthy, S.C., Chanda, P.K., Nigida, S.M., Markham, P.D., Zolla-Pazner, S., Steimer, K., Wade, M., Reitz, M.S., Arthur, L.O., Mizutani, S., Davis, A., Hung, P.P., Gallo, R.C., Eichberg, J., Robert-Guroff, M. Nat. Med. (1997) [Pubmed]
  6. Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability. Li, X., Manley, J.L. Cell (2005) [Pubmed]
  7. ASF/SF2-regulated CaMKIIdelta alternative splicing temporally reprograms excitation-contraction coupling in cardiac muscle. Xu, X., Yang, D., Ding, J.H., Wang, W., Chu, P.H., Dalton, N.D., Wang, H.Y., Bermingham, J.R., Ye, Z., Liu, F., Rosenfeld, M.G., Manley, J.L., Ross, J., Chen, J., Xiao, R.P., Cheng, H., Fu, X.D. Cell (2005) [Pubmed]
  8. Binding sites for Rev and ASF/SF2 map to a 55-nucleotide purine-rich exonic element in equine infectious anemia virus RNA. Chung H, n.u.l.l., Derse, D. J. Biol. Chem. (2001) [Pubmed]
  9. Cross-reactive lysis of human targets infected with prototypic and clinical human immunodeficiency virus type 1 (HIV-1) strains by murine anti-HIV-1 IIIB env-specific cytotoxic T lymphocytes. Chada, S., DeJesus, C.E., Townsend, K., Lee, W.T., Laube, L., Jolly, D.J., Chang, S.M., Warner, J.F. J. Virol. (1993) [Pubmed]
  10. A C-terminal helicase domain of the human papillomavirus E1 protein binds E2 and the DNA polymerase alpha-primase p68 subunit. Masterson, P.J., Stanley, M.A., Lewis, A.P., Romanos, M.A. J. Virol. (1998) [Pubmed]
  11. Farnesyltransferase inhibitor, R115777, reverses the resistance of human glioma cell lines to ionizing radiation. Delmas, C., Heliez, C., Cohen-Jonathan, E., End, D., Bonnet, J., Favre, G., Toulas, C. Int. J. Cancer (2002) [Pubmed]
  12. A multistep procedure for the chemical inactivation of human immunodeficiency virus for use as an experimental vaccine. Race, E., Stein, C.A., Wigg, M.D., Baksh, A., Addawe, M., Frezza, P., Oxford, J.S. Vaccine (1995) [Pubmed]
  13. The SR splicing factors ASF/SF2 and SC35 have antagonistic effects on intronic enhancer-dependent splicing of the beta-tropomyosin alternative exon 6A. Gallego, M.E., Gattoni, R., Stévenin, J., Marie, J., Expert-Bezançon, A. EMBO J. (1997) [Pubmed]
  14. Modulation of exon skipping and inclusion by heterogeneous nuclear ribonucleoprotein A1 and pre-mRNA splicing factor SF2/ASF. Mayeda, A., Helfman, D.M., Krainer, A.R. Mol. Cell. Biol. (1993) [Pubmed]
  15. The subcellular localization of SF2/ASF is regulated by direct interaction with SR protein kinases (SRPKs). Koizumi, J., Okamoto, Y., Onogi, H., Mayeda, A., Krainer, A.R., Hagiwara, M. J. Biol. Chem. (1999) [Pubmed]
  16. hnRNP A1 and the SR proteins ASF/SF2 and SC35 have antagonistic functions in splicing of beta-tropomyosin exon 6B. Expert-Bezançon, A., Sureau, A., Durosay, P., Salesse, R., Groeneveld, H., Lecaer, J.P., Marie, J. J. Biol. Chem. (2004) [Pubmed]
  17. Alternative splicing of the adenylyl cyclase stimulatory G-protein G alpha(s) is regulated by SF2/ASF and heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) and involves the use of an unusual TG 3'-splice Site. Pollard, A.J., Krainer, A.R., Robson, S.C., Europe-Finner, G.N. J. Biol. Chem. (2002) [Pubmed]
  18. Chromosomal localization of mouse and human genes encoding the splicing factors ASF/SF2 (SFRS1) and SC-35 (SFRS2). Bermingham, J.R., Arden, K.C., Naumova, A.K., Sapienza, C., Viars, C.S., Fu, X.D., Khotz, J., Manley, J.L., Rosenfeld, M.G. Genomics (1995) [Pubmed]
  19. Specific commitment of different pre-mRNAs to splicing by single SR proteins. Fu, X.D. Nature (1993) [Pubmed]
  20. Loss of splicing factor ASF/SF2 induces G2 cell cycle arrest and apoptosis, but inhibits internucleosomal DNA fragmentation. Li, X., Wang, J., Manley, J.L. Genes Dev. (2005) [Pubmed]
  21. The human splicing factors ASF/SF2 and SC35 possess distinct, functionally significant RNA binding specificities. Tacke, R., Manley, J.L. EMBO J. (1995) [Pubmed]
  22. A serine/arginine-rich domain in the human U1 70k protein is necessary and sufficient for ASF/SF2 binding. Cao, W., Garcia-Blanco, M.A. J. Biol. Chem. (1998) [Pubmed]
  23. Exonic splicing enhancer-dependent selection of the bovine papillomavirus type 1 nucleotide 3225 3' splice site can be rescued in a cell lacking splicing factor ASF/SF2 through activation of the phosphatidylinositol 3-kinase/Akt pathway. Liu, X., Mayeda, A., Tao, M., Zheng, Z.M. J. Virol. (2003) [Pubmed]
  24. Pre-mRNA splicing in plants: characterization of Ser/Arg splicing factors. Lopato, S., Mayeda, A., Krainer, A.R., Barta, A. Proc. Natl. Acad. Sci. U.S.A. (1996) [Pubmed]
  25. SR protein kinase 1 is resilient to inactivation. Ngo, J.C., Gullingsrud, J., Giang, K., Yeh, M.J., Fu, X.D., Adams, J.A., McCammon, J.A., Ghosh, G. Structure (2007) [Pubmed]
  26. A novel transcriptional coactivator, p52, functionally interacts with the essential splicing factor ASF/SF2. Ge, H., Si, Y., Wolffe, A.P. Mol. Cell (1998) [Pubmed]
  27. A bidirectional SF2/ASF- and SRp40-dependent splicing enhancer regulates human immunodeficiency virus type 1 rev, env, vpu, and nef gene expression. Caputi, M., Freund, M., Kammler, S., Asang, C., Schaal, H. J. Virol. (2004) [Pubmed]
  28. Mass spectrometric and kinetic analysis of ASF/SF2 phosphorylation by SRPK1 and Clk/Sty. Velazquez-Dones, A., Hagopian, J.C., Ma, C.T., Zhong, X.Y., Zhou, H., Ghosh, G., Fu, X.D., Adams, J.A. J. Biol. Chem. (2005) [Pubmed]
  29. Differential effects of the SR proteins 9G8, SC35, ASF/SF2, and SRp40 on the utilization of the A1 to A5 splicing sites of HIV-1 RNA. Ropers, D., Ayadi, L., Gattoni, R., Jacquenet, S., Damier, L., Branlant, C., Stévenin, J. J. Biol. Chem. (2004) [Pubmed]
  30. 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. Labourier, E., Rossi, F., Gallouzi, I.E., Allemand, E., Divita, G., Tazi, J. Nucleic Acids Res. (1998) [Pubmed]
  31. Cloning of human PRP4 reveals interaction with Clk1. Kojima, T., Zama, T., Wada, K., Onogi, H., Hagiwara, M. J. Biol. Chem. (2001) [Pubmed]
  32. A subset of SR proteins activates splicing of the cardiac troponin T alternative exon by direct interactions with an exonic enhancer. Ramchatesingh, J., Zahler, A.M., Neugebauer, K.M., Roth, M.B., Cooper, T.A. Mol. Cell. Biol. (1995) [Pubmed]
  33. Expression of splicing factors in human ovarian cancer. Fischer, D.C., Noack, K., Runnebaum, I.B., Watermann, D.O., Kieback, D.G., Stamm, S., Stickeler, E. Oncol. Rep. (2004) [Pubmed]
  34. Molecular cloning, polymorphism and mapping of the porcine SFRS1 gene. Wang, H., Wang, H.L., Zhu, Z.M., Yang, S.L., Li, K. Anim. Genet. (2005) [Pubmed]
  35. Multiple factors including the small nuclear ribonucleoproteins U1 and U2 are necessary for pre-mRNA splicing in vitro. Krainer, A.R., Maniatis, T. Cell (1985) [Pubmed]
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