Pelisch, F.; Gerez, J.; Druker, J.; Schor, I.E.; Muñoz, M.J.; Risso, G.; Petrillo, E.; Westman, B.J.; Lamond, A.I.; Arzt, E.; Srebrow, A. "The serine/arginine-rich protein SF2/ASF regulates protein sumoylation" (2010) Proceedings of the National Academy of Sciences of the United States of America. 107(37):16119-16124
Artículo de Acceso Abierto. Puede ser descargado en su versión final
Consulte el artículo en la página del editor
Consulte la política de Acceso Abierto del editor


Protein modification by conjugation of small ubiquitin-related modifier (SUMO) is involved in diverse biological functions, such as transcription regulation, subcellular partitioning, stress response, DNA damage repair, and chromatin remodeling. Here, we show that the serine/arginine-rich protein SF2/ASF, a factor involved in splicing regulation and other RNA metabolism-related processes, is a regulator of the sumoylation pathway. The overexpression of this protein stimulates, but its knockdown inhibits SUMO conjugation. SF2/ASF interacts with Ubc9 and enhances sumoylation of specific substrates, sharing characteristics with already described SUMO E3 ligases. In addition, SF2/ASF interacts with the SUMO E3 ligase PIAS1 (protein inhibitor of activated STAT-1), regulating PIAS1-induced overall protein sumoylation. The RNA recognition motif 2 of SF2/ASF is necessary and sufficient for sumoylation enhancement. Moreover, SF2/ASF has a role in heat shock-induced sumoylation and promotes SUMO conjugation to RNA processing factors. These results add a component to the sumoylation pathway and a previously unexplored role for the multifunctional SR protein SF2/ASF.


Documento: Artículo
Título:The serine/arginine-rich protein SF2/ASF regulates protein sumoylation
Autor:Pelisch, F.; Gerez, J.; Druker, J.; Schor, I.E.; Muñoz, M.J.; Risso, G.; Petrillo, E.; Westman, B.J.; Lamond, A.I.; Arzt, E.; Srebrow, A.
Filiación:Laboratorio de Fisiología Y Biología Molecular, Instituto de Fisiología, Biologia Molecular Y Neurociencias, Consejo Nacional de Investigaciones Cientificas Y Tecnicas, Argentina
Departamento de Fisiología, Biología Molecular Y Celular, Facultad de Ciencias Exactas Y Naturales, Universidad de Buenos Aires, Pabellón II, C1428EHA Buenos Aires, Argentina
College of Life Sciences, University of Dundee, Dundee DD1 5EH, United Kingdom
Palabras clave:E3 ligase; Posttranslational modification; RNA processing; Splicing factor; protein asf; protein inhibitor of activated STAT; protein inhibitor of activated STAT1; protein sf2; protein Ubc9; regulator protein; RNA; SUMO E3 ligase; SUMO protein; ubiquitin protein ligase E3; unclassified drug; nuclear protein; protein binding; protein p53; RNA binding protein; serine-arginine-rich splicing proteins; small interfering RNA; SUMO 1 protein; ubiquitin conjugating enzyme; ubiquitin-conjugating enzyme UBC9; article; conjugation; controlled study; enzyme activity; heat shock; human; human cell; molecular recognition; priority journal; protein expression; protein function; protein processing; protein protein interaction; regulatory mechanism; RNA metabolism; RNA splicing; signal transduction; sumoylation; cell line; enzyme specificity; genetics; heat shock response; metabolism; Cell Line; Heat-Shock Response; Humans; Nuclear Proteins; Protein Binding; RNA, Small Interfering; RNA-Binding Proteins; Substrate Specificity; SUMO-1 Protein; Tumor Suppressor Protein p53; Ubiquitin-Conjugating Enzymes
Página de inicio:16119
Página de fin:16124
Título revista:Proceedings of the National Academy of Sciences of the United States of America
Título revista abreviado:Proc. Natl. Acad. Sci. U. S. A.
CAS:RNA, 63231-63-0; SUMO 1 protein, 182213-10-1; ubiquitin conjugating enzyme, 147154-16-3; Nuclear Proteins; RNA, Small Interfering; RNA-Binding Proteins; serine-arginine-rich splicing proteins; SUMO-1 Protein; Tumor Suppressor Protein p53; ubiquitin-conjugating enzyme UBC9; Ubiquitin-Conjugating Enzymes


  • Graveley, B.R., Sorting out the complexity of SR protein functions (2000) RNA, 6, pp. 1197-1211
  • Zhong, X.Y., Wang, P., Han, J., Rosenfeld, M.G., Fu, X.D., SR proteins in vertical integration of gene expression from transcription to RNA processing to translation (2009) Mol Cell, 35, pp. 1-10
  • Shen, H., Green, M.R., A pathway of sequential Arginine-Serine-Rich Domain-Splicing signal interactions during mammalian spliceosome assembly (2004) Molecular Cell, 16 (3), pp. 363-373. , DOI 10.1016/j.molcel.2004.10.021, PII S1097276504006379
  • Shen, H., Kan, J.L.C., Green, M.R., Arginine-Serine-Rich Domains Bound at Splicing Enhancers Contact the Branchpoint to Promote Prespliceosome Assembly (2004) Molecular Cell, 13 (3), pp. 367-376. , DOI 10.1016/S1097-2765(04)00025-5
  • Michlewski, G., Sanford, J.R., Caceres, J.F., The Splicing Factor SF2/ASF Regulates Translation Initiation by Enhancing Phosphorylation of 4E-BP1 (2008) Molecular Cell, 30 (2), pp. 179-189. , DOI 10.1016/j.molcel.2008.03.013, PII S1097276508002372
  • Long, J.C., Caceres, J.F., The SR protein family of splicing factors: Master regulators of gene expression (2009) Biochem J, 417, pp. 15-27
  • Lin, S., Coutinho-Mansfield, G., Wang, D., Pandit, S., Fu, X.D., The splicing factor SC35 has an active role in transcriptional elongation (2008) Nat Struct Mol Biol, 15, pp. 819-826
  • Huang, Y., Yario, T.A., Steitz, J.A., A molecular linkbetween SR protein dephosphorylation and mRNA export (2004) Proc Natl Acad Sci USA, 101, pp. 9666-9670
  • Lemaire, R., Stability of a PKCI-1-related mRNA is controlled by the splicing factor ASF/SF2: A novel function for SR proteins (2002) Genes Dev, 16, pp. 594-607
  • Zhang, Z., Krainer, A.R., Involvement of SR proteins in mRNA surveillance (2004) Mol Cell, 16, pp. 597-607
  • Sanford, J.R., Gray, N.K., Beckmann, K., Caceres, J.F., A novel role for shuttling SR proteins in mRNA translation (2004) Genes and Development, 18 (7), pp. 755-768. , DOI 10.1101/gad.286404
  • Li, X., Manley, J.L., Inactivation of the SR protein splicing factor ASF/SF2 results in genomic instability (2005) Cell, 122, pp. 365-378
  • Li, X., Wang, J., Manley, J.L., Loss of splicing factor ASF/SF2 induces G2 cell cycle arrest and apoptosis, but inhibits internucleosomal DNA fragmentation (2005) Genes Dev, 19, pp. 2705-2714
  • Manley, J.L., Krainer, A.R., A rational nomenclature for serine/arginine-rich protein splicing factors (SR proteins) (2010) Genes Dev, 24, pp. 1073-1074
  • Ge, H., Manley, J.L., A protein factor, ASF, controls cell-specific alternative splicing of SV40 early pre-mRNA in vitro (1990) Cell, 62 (1), pp. 25-34. , DOI 10.1016/0092-8674(90)90236-8
  • Krainer, A.R., Conway, G.C., Kozak, D., Purification and characterization of pre-mRNA splicing factor SF2 from HeLa cells (1990) Genes and Development, 4 (7), pp. 1158-1171
  • Chiodi, I., RNA recognition motif 2 directs the recruitment of SF2/ASF to nuclear stress bodies (2004) Nucleic Acids Res, 32, pp. 4127-4136
  • Metz, A., Soret, J., Vourc'h, C., Tazi, J., Jolly, C., A key role for stress-induced satellite III transcripts in the relocalization of splicing factors into nuclear stress granules (2004) J Cell Sci, 117, pp. 4551-4558
  • Geiss-Friedlander, R., Melchior, F., Concepts in sumoylation: A decade on (2007) Nat Rev Mol Cell Biol, 8, pp. 947-956
  • Hay, R.T., SUMO: A history of modification (2005) Mol Cell, 18, pp. 1-12
  • Seeler, J.S., Dejean, A., Nuclear and unclear functions of SUMO (2003) Nat Rev Mol Cell Biol, 4, pp. 690-699
  • Melchior, F., Schergaut, M., Pichler, A., SUMO: Ligases, isopeptidases and nuclear pores (2003) Trends Biochem Sci, 28, pp. 612-618
  • Johnson, E.S., Protein modification by SUMO (2004) Annu Rev Biochem, 73, pp. 355-382
  • Desterro, J.M.P., Thomson, J., Hay, R.T., Ubch9 conjugates SUMO but not ubiquitin (1997) FEBS Letters, 417 (3), pp. 297-300. , DOI 10.1016/S0014-5793(97)01305-7, PII S0014579397013057
  • Lin, D., Identification of a substrate recognition site on Ubc9 (2002) J Biol Chem, 277, pp. 21740-21748
  • Hochstrasser, M., SP-RING for SUMO: New functions bloom for a ubiquitin-like protein (2001) Cell, 107, pp. 5-8
  • Kagey, M.H., Melhuish, T.A., Wotton, D., The polycomb protein Pc2 is a SUMO E3 (2003) Cell, 113, pp. 127-137
  • Pichler, A., Gast, A., Seeler, J.S., Dejean, A., Melchior, F., The nucleoporin RanBP2 has SUMO1 E3 ligase activity (2002) Cell, 108, pp. 109-120
  • Palvimo, J.J., PIAS proteins as regulators of small ubiquitin-related modifier (SUMO) modifications and transcription (2007) Biochem Soc Trans, 35, pp. 1405-1408
  • Carbia-Nagashima, A., Gerez, J., Perez-Castro, C., Paez-Pereda, M., Silberstein, S., Stalla, G.K., Holsboer, F., Arzt, E., RSUME, a Small RWD-Containing Protein, Enhances SUMO Conjugation and Stabilizes HIF-1alpha during Hypoxia (2007) Cell, 131 (2), pp. 309-323. , DOI 10.1016/j.cell.2007.07.044, PII S0092867407010240
  • Joazeiro, C.A., Weissman, A.M., RING finger proteins: Mediators of ubiquitin ligase activity (2000) Cell, 102, pp. 549-552
  • Ihara, M., Stein, P., Schultz, R.M., UBE2I (UBC9), a SUMO-conjugating enzyme, localizes to nuclear speckles and stimulates transcription in mouse oocytes (2008) Biol Reprod, 79, pp. 906-913
  • Nayler, O., Stratling, W., Bourquin, J.-P., Stagljar, I., Lindemann, L., Jasper, H., Hartmann, A.M., Stamm, S., SAF-B protein couples transcription and pre-mRNA splicing to SAR/MAR elements (1998) Nucleic Acids Research, 26 (15), pp. 3542-3549. , DOI 10.1093/nar/26.15.3542
  • Rappsilber, J., Ryder, U., Lamond, A.I., Mann, M., Large-scale proteomic analysis of the human spliceosome (2002) Genome Res, 12, pp. 1231-1245
  • Tan, J.A., Protein inhibitors of activated STAT resemble scaffold attachment factors and function as interacting nuclear receptor coregulators (2002) J Biol Chem, 277, pp. 16993-17001
  • Blaustein, M., Concerted regulation of nuclear and cytoplasmic activities of SR proteins by AKT (2005) Nat Struct Mol Biol, 12, pp. 1037-1044
  • Blaustein, M., SF2/ASF regulates proteomic diversity by affecting the balance between translation initiation mechanisms (2009) J Cell Biochem, 107, pp. 826-833
  • Johnson, E.S., Gupta, A.A., An E3-like factor that promotes SUMO conjugation to the yeast septins (2001) Cell, 106 (6), pp. 735-744. , DOI 10.1016/S0092-8674(01)00491-3
  • Hammer, E., Heilbronn, R., Weger, S., The E3 ligase Topors induces the accumulation of polysumoylated forms of DNA topoisomerase I in vitro and in vivo (2007) FEBS Letters, 581 (28), pp. 5418-5424. , DOI 10.1016/j.febslet.2007.10.040, PII S0014579307011052
  • Rodriguez, M.S., SUMO-1 modification activates the transcriptional response of p53 (1999) EMBO J, 18, pp. 6455-6461
  • Weger, S., Hammer, E., Heilbronn, R., Topors acts as a SUMO-1 E3 ligase for p53 in vitro and in vivo (2005) FEBS Letters, 579 (22), pp. 5007-5012. , DOI 10.1016/j.febslet.2005.07.088, PII S0014579305009774
  • Labourier, E., 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 (1998) Nucleic Acids Res, 26, pp. 2955-2962
  • Kowalska-Loth, B., Girstun, A., Trzcińska, A.M., Piekiełko- Witkowska, A., Staroń, K., SF2/ASF protein binds to the cap region of human topoisomerase I through two RRM domains (2005) Biochem Biophys Res Commun, 331, pp. 398-403
  • Yunus, A.A., Lima, C.D., Lysine activation and functional analysis of E2-mediated conjugation in the SUMO pathway (2006) Nat Struct Mol Biol, 13, pp. 491-499
  • Tempé, D., Piechaczyk, M., Bossis, G., SUMO under stress (2008) Biochem Soc Trans, 36, pp. 874-878
  • Golebiowski, F., System-wide changes to SUMO modifications in response to heat shock (2009) Sci Signal, 2, pp. ra24
  • Denegri, M., Chiodi, I., Corioni, M., Cobianchi, F., Riva, S., Biamonti, G., Stress-induced nuclear bodies are sites of accumulation of pre-mRNA processing factors (2001) Molecular Biology of the Cell, 12 (11), pp. 3502-3514
  • Biamonti, G., Nuclear stress bodies: A heterochromatin affair? (2004) Nat Rev Mol Cell Biol, 5, pp. 493-498
  • Chen, T., Boisvert, F.-M., Bazett-Jones, D.P., Richard, S., A role for the GSG domain in localizing Sam68 to novel nuclear structures in cancer cell lines (1999) Molecular Biology of the Cell, 10 (9), pp. 3015-3033
  • Poukka, H., Karvonen, U., Janne, O.A., Palvimo, J.J., Covalent modification of the androgen receptor by small ubiquitin-like modifier 1 (SUMO-1) (2000) Proc Natl Acad Sci USA, 97, pp. 14145-14150
  • Li, T., Sumoylation of heterogeneous nuclear ribonucleoproteins, zinc finger proteins, and nuclear pore complex proteins: A proteomic analysis (2004) Proc Natl Acad Sci USA, 101, pp. 8551-8556
  • Navascues, J., SUMO-1 transiently localizes to Cajal bodies in mammalian neurons (2008) J Struct Biol, 163, pp. 137-146
  • Vassileva, M.T., Matunis, M.J., SUMO modification of heterogeneous nuclear ribonucleoproteins (2004) Mol Cell Biol, 24, pp. 3623-3632
  • Vertegaal, A.C., A proteomic study of SUMO-2 target proteins (2004) J Biol Chem, 279, pp. 33791-33798
  • Blomster, H.A., Novel proteomics strategy brings insight into the prevalence of SUMO-2 target sites (2009) Mol Cell Proteomics, 8, pp. 1382-1390
  • Pungaliya, P., Kulkarni, D., Park, H.-J., Marshall, H., Zheng, H., Lackland, H., Saleem, A., Rubin, E.H., TOPORS functions as a SUMO-1 E3 ligase for chromatin-modifying proteins (2007) Journal of Proteome Research, 6 (10), pp. 3918-3923. , DOI 10.1021/pr0703674
  • Babic, I., Cherry, E., Fujita, D.J., SUMO modification of Sam68 enhances its ability to repress cyclin D1 expression and inhibits its ability to induce apoptosis (2006) Oncogene, 25, pp. 4955-4964
  • Lyman, S.K., Gerace, L., Baserga, S.J., Human Nop5/Nop58 is a component common to the box C/D small nucleolar ribonucleoproteins (1999) RNA, 5, pp. 1597-1604
  • Rajan, P., Gaughan, L., Dalgliesh, C., El-Sherif, A., Robson, C.N., Leung, H.Y., Elliott, D.J., Regulation of gene expression by the RNA-binding protein Sam68 in cancer (2008) Biochemical Society Transactions, 36 (3), pp. 505-507. , DOI 10.1042/BST0360505
  • Desterro, J.M.P., Keegan, L.P., Jaffray, E., Hay, R.T., O'Connell, M.A., Carmo-Fonseca, M., SUMO-1 modification alters ADAR1 editing activity (2005) Molecular Biology of the Cell, 16 (11), pp. 5115-5126. , DOI 10.1091/mbc.E05-06-0536
  • Vethantham, V., Rao, N., Manley, J.L., Sumoylation regulates multiple aspects of mammalian poly(A) polymerase function (2008) Genes Dev, 22, pp. 499-511
  • Vethantham, V., Rao, N., Manley, J.L., Sumoylation modulates the assembly and activity of the pre-mRNA 3′ processing complex (2007) Mol Cell Biol, 27, pp. 8848-8858
  • Mo, Y.Y., Yu, Y., Shen, Z., Beck, W.T., Nucleolar delocalization of human topoisomerase I in response to topotecan correlates with sumoylation of the protein (2002) J Biol Chem, 277, pp. 2958-2964
  • Haindl, M., Harasim, T., Eick, D., Muller, S., The nucleolar SUMO-specific protease SENP3 reverses SUMO modification of nucleophosmin and is required for rRNA processing (2008) EMBO Reports, 9 (3), pp. 273-279. , DOI 10.1038/embor.2008.3, PII EMBOR20083
  • Cazalla, D., Sanford, J.R., Cáceres, J.F., A rapid and efficient protocol to purify biologically active recombinant proteins frommammalian cells (2005) Protein Expr Purif, 42, pp. 54-58
  • Pichler, A., Knipscheer, P., Saitoh, H., Sixma, T.K., Melchior, F., The RanBP2 SUMO E3 ligase is neither HECT- nor RING-type (2004) Nat Struct Mol Biol, 11, pp. 984-991


---------- APA ----------
Pelisch, F., Gerez, J., Druker, J., Schor, I.E., Muñoz, M.J., Risso, G., Petrillo, E.,..., Srebrow, A. (2010) . The serine/arginine-rich protein SF2/ASF regulates protein sumoylation. Proceedings of the National Academy of Sciences of the United States of America, 107(37), 16119-16124.
---------- CHICAGO ----------
Pelisch, F., Gerez, J., Druker, J., Schor, I.E., Muñoz, M.J., Risso, G., et al. "The serine/arginine-rich protein SF2/ASF regulates protein sumoylation" . Proceedings of the National Academy of Sciences of the United States of America 107, no. 37 (2010) : 16119-16124.
---------- MLA ----------
Pelisch, F., Gerez, J., Druker, J., Schor, I.E., Muñoz, M.J., Risso, G., et al. "The serine/arginine-rich protein SF2/ASF regulates protein sumoylation" . Proceedings of the National Academy of Sciences of the United States of America, vol. 107, no. 37, 2010, pp. 16119-16124.
---------- VANCOUVER ----------
Pelisch, F., Gerez, J., Druker, J., Schor, I.E., Muñoz, M.J., Risso, G., et al. The serine/arginine-rich protein SF2/ASF regulates protein sumoylation. Proc. Natl. Acad. Sci. U. S. A. 2010;107(37):16119-16124.