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U2AF2  -  U2 small nuclear RNA auxiliary factor 2

Homo sapiens

Synonyms: Splicing factor U2AF 65 kDa subunit, U2 auxiliary factor 65 kDa subunit, U2 snRNP auxiliary factor large subunit, U2AF65, hU2AF(65), ...
 
 
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Disease relevance of U2AF2

  • After adenovirus infection, U2AF65 redistributes from the speckles and is prefferentially detected at sites of viral transcription [1].
  • Human immunodeficiency virus type 1 hnRNP A/B-dependent exonic splicing silencer ESSV antagonizes binding of U2AF65 to viral polypyrimidine tracts [2].
 

High impact information on U2AF2

  • A novel peptide recognition mode revealed by the X-ray structure of a core U2AF35/U2AF65 heterodimer [3].
  • Our results show that SF1 interacts strongly with human U2AF65, and that SF1 is a bona fide E complex component [4].
  • A complementary DNA clone encoding the large subunit of the essential mammalian pre-messenger RNA splicing component U2 snRNP auxiliary factor (U2AF65) has been isolated and expressed in vitro [5].
  • Interaction of U2AF65 RS region with pre-mRNA branch point and promotion of base pairing with U2 snRNA [corrected] [6].
  • The uridine-rich degenerate sequences selected by U2AF65 are similar to those present in the diverse array of natural metazoan Py-tracts [7].
 

Biological context of U2AF2

  • U2AF65 binds to RNA at the polypyrimidine tract, whereas U2AF35 is thought to interact through its arginine/serine-rich (RS) domain with other RS-domain-containing factors bound at the 5' splice site, assembled in splicing enhancer complexes, or associated with the U4/U6.U5 small nuclear ribonucleoprotein complex [8].
  • Steroid hormone receptor coactivation and alternative RNA splicing by U2AF65-related proteins CAPERalpha and CAPERbeta [9].
  • The association of U2AF65 with speckles persists during mitosis, when transcription and splicing are downregulated [1].
  • Similarly to TAP, U2AF65 stimulated directly the nuclear export and expression of an mRNA that is otherwise retained in the nucleus [10].
  • Multiple U2AF65 binding sites within SF3b155: thermodynamic and spectroscopic characterization of protein-protein interactions among pre-mRNA splicing factors [11].
 

Anatomical context of U2AF2

  • These results suggest a new role for PKG in mammalian pre-mRNA splicing by regulating in a phosphorylation-dependent manner the association of SF1 with U2AF65 and spliceosome assembly [12].
  • Both U2AF65 and U2AF35 are concentrated in a small number of nuclear foci corresponding to coiled bodies, subnuclear organelles first identified by light microscopy in 1903 [13].
  • Using two different approaches for measuring FRET, we have identified and spatially localized sites of direct interaction between U2AF35 and U2AF65 in vivo in live cell nuclei [14].
  • We observe that the U2AF65 (S) variant predominates in a variety of tissues and cell lines, and is generated together with the U2AF65 (L) form (2) by alternative 5' splice site selection from a single gene [15].
  • Our results show that 10% of cellular mRNAs expressed in HeLa cells associate differentially with U2AF65 and PTB [16].
 

Associations of U2AF2 with chemical compounds

  • The X-ray structure of the human core U2AF heterodimer, consisting of the U2AF35 central domain and a proline-rich region of U2AF65, has been determined at 2.2 A resolution [3].
  • The structure reveals a novel protein-protein recognition strategy, in which an atypical RNA recognition motif (RRM) of U2AF35 and the U2AF65 polyproline segment interact via reciprocal "tongue-in-groove" tryptophan residues [3].
  • The site-specific pyrimidine tract binding activity of the U2AF heterodimer has previously been assigned to hU2AF65 [17].
  • U2 snRNP Auxiliary Factor (U2AF) is an essential pre-mRNA splicing factor complex, comprising 35-kDa (U2AF35) and 65-kDa (U2AF65) subunits [14].
  • Furthermore, overexpression of the truncated U2AF65, which contains the arginine and serine dipeptide-rich domain and linker domain, but lacks the RNA binding domain, selectively inhibits the IDDE-mediated N30 inclusion in mRNA from the wild-type minigene in a dominant negative fashion [18].
 

Physical interactions of U2AF2

  • A protein related to splicing factor U2AF35 that interacts with U2AF65 and SR proteins in splicing of pre-mRNA [8].
  • Interestingly a mutation associated with DDS enhanced both -KTS WT1 binding to U2AF65 and splicing-factor colocalization [19].
  • Thus, PSF may replace the 3' splice site binding factor U2AF65 which is destabilized during spliceosome assembly [20].
  • The Polypyrimidine Tract Binding Protein (PTB) Represses Splicing of Exon 6B from the {beta}-Tropomyosin Pre-mRNA by Directly Interfering with the Binding of the U2AF65 Subunit [21].
  • That is, a natural deficiency in binding U2AF65 to the 3' splice site that leads to exon skipping might be overcome by a mechanism in which U1 snRNP facilitates the binding of U2AF65 through a network of template-directed and exon-bridging interactions [22].
 

Regulatory relationships of U2AF2

  • Our results indicate that neural cell adhesion molecule 5' splice site sequences influence U2AF65 binding through a U1 small nuclear ribonucleoprotein/U2AF interaction that occurs at the commitment stage of spliceosome assembly, before stable binding of the U2 small nuclear ribonucleoprotein [23].
 

Other interactions of U2AF2

  • The encoded proteins share the U2AF65 interaction domain, a hnRNP K homology domain, and one or two zinc knuckles required for RNA binding as well as Pro-rich C-terminal sequences with their yeast and mammalian counterparts [24].
  • We show that UAP56 is an essential splicing factor, which is recruited to the pre-mRNA dependent on U2AF65, and is required for the U2 snRNP-branchpoint interaction [25].
  • We further found in human cells that the exogenously expressed large U2AF subunit, U2AF65, accumulates in spliced mRNP, leading to the recruitment of U2AF35 and TAP [10].
  • Our results reveal a new function of U2AF65: to position a DEAD box protein required for U2 snRNP binding at the pre-mRNA branchpoint region [25].
  • Although generally considered a transcription factor this study has revealed that WT1 interacts with an essential splicing factor, U2AF65, and associates with the splicing machinery [19].
 

Analytical, diagnostic and therapeutic context of U2AF2

References

  1. Targeting of U2AF65 to sites of active splicing in the nucleus. Gama-Carvalho, M., Krauss, R.D., Chiang, L., Valcárcel, J., Green, M.R., Carmo-Fonseca, M. J. Cell Biol. (1997) [Pubmed]
  2. Human immunodeficiency virus type 1 hnRNP A/B-dependent exonic splicing silencer ESSV antagonizes binding of U2AF65 to viral polypyrimidine tracts. Domsic, J.K., Wang, Y., Mayeda, A., Krainer, A.R., Stoltzfus, C.M. Mol. Cell. Biol. (2003) [Pubmed]
  3. A novel peptide recognition mode revealed by the X-ray structure of a core U2AF35/U2AF65 heterodimer. Kielkopf, C.L., Rodionova, N.A., Green, M.R., Burley, S.K. Cell (2001) [Pubmed]
  4. Cross-intron bridging interactions in the yeast commitment complex are conserved in mammals. Abovich, N., Rosbash, M. Cell (1997) [Pubmed]
  5. Cloning and domain structure of the mammalian splicing factor U2AF. Zamore, P.D., Patton, J.G., Green, M.R. Nature (1992) [Pubmed]
  6. Interaction of U2AF65 RS region with pre-mRNA branch point and promotion of base pairing with U2 snRNA [corrected]. Valcárcel, J., Gaur, R.K., Singh, R., Green, M.R. Science (1996) [Pubmed]
  7. Distinct binding specificities and functions of higher eukaryotic polypyrimidine tract-binding proteins. Singh, R., Valcárcel, J., Green, M.R. Science (1995) [Pubmed]
  8. A protein related to splicing factor U2AF35 that interacts with U2AF65 and SR proteins in splicing of pre-mRNA. Tronchère, H., Wang, J., Fu, X.D. Nature (1997) [Pubmed]
  9. Steroid hormone receptor coactivation and alternative RNA splicing by U2AF65-related proteins CAPERalpha and CAPERbeta. Dowhan, D.H., Hong, E.P., Auboeuf, D., Dennis, A.P., Wilson, M.M., Berget, S.M., O'Malley, B.W. Mol. Cell (2005) [Pubmed]
  10. U2AF participates in the binding of TAP (NXF1) to mRNA. Zolotukhin, A.S., Tan, W., Bear, J., Smulevitch, S., Felber, B.K. J. Biol. Chem. (2002) [Pubmed]
  11. Multiple U2AF65 binding sites within SF3b155: thermodynamic and spectroscopic characterization of protein-protein interactions among pre-mRNA splicing factors. Thickman, K.R., Swenson, M.C., Kabogo, J.M., Gryczynski, Z., Kielkopf, C.L. J. Mol. Biol. (2006) [Pubmed]
  12. Phosphorylation of splicing factor SF1 on Ser20 by cGMP-dependent protein kinase regulates spliceosome assembly. Wang, X., Bruderer, S., Rafi, Z., Xue, J., Milburn, P.J., Krämer, A., Robinson, P.J. EMBO J. (1999) [Pubmed]
  13. Cloning and intracellular localization of the U2 small nuclear ribonucleoprotein auxiliary factor small subunit. Zhang, M., Zamore, P.D., Carmo-Fonseca, M., Lamond, A.I., Green, M.R. Proc. Natl. Acad. Sci. U.S.A. (1992) [Pubmed]
  14. FRET analyses of the U2AF complex localize the U2AF35/U2AF65 interaction in vivo and reveal a novel self-interaction of U2AF35. Chusainow, J., Ajuh, P.M., Trinkle-Mulcahy, L., Sleeman, J.E., Ellenberg, J., Lamond, A.I. RNA (2005) [Pubmed]
  15. Biochemical properties of a novel U2AF65 protein isoform generated by alternative RNA splicing. Ding, F., Hagan, J.P., Wang, Z., Grabowski, P.J. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  16. Genome-wide identification of functionally distinct subsets of cellular mRNAs associated with two nucleocytoplasmic-shuttling mammalian splicing factors. Gama-Carvalho, M., Barbosa-Morais, N.L., Brodsky, A.S., Silver, P.A., Carmo-Fonseca, M. Genome Biol. (2006) [Pubmed]
  17. RNA binding activity of heterodimeric splicing factor U2AF: at least one RS domain is required for high-affinity binding. Rudner, D.Z., Breger, K.S., Kanaar, R., Adams, M.D., Rio, D.C. Mol. Cell. Biol. (1998) [Pubmed]
  18. An intronic downstream enhancer promotes 3' splice site usage of a neural cell-specific exon. Guo, N., Kawamoto, S. J. Biol. Chem. (2000) [Pubmed]
  19. WT1 interacts with the splicing factor U2AF65 in an isoform-dependent manner and can be incorporated into spliceosomes. Davies, R.C., Calvio, C., Bratt, E., Larsson, S.H., Lamond, A.I., Hastie, N.D. Genes Dev. (1998) [Pubmed]
  20. A novel set of spliceosome-associated proteins and the essential splicing factor PSF bind stably to pre-mRNA prior to catalytic step II of the splicing reaction. Gozani, O., Patton, J.G., Reed, R. EMBO J. (1994) [Pubmed]
  21. The Polypyrimidine Tract Binding Protein (PTB) Represses Splicing of Exon 6B from the {beta}-Tropomyosin Pre-mRNA by Directly Interfering with the Binding of the U2AF65 Subunit. Sauli??re, J., Sureau, A., Expert-Bezan??on, A., Marie, J. Mol. Cell. Biol. (2006) [Pubmed]
  22. U1 snRNP targets an essential splicing factor, U2AF65, to the 3' splice site by a network of interactions spanning the exon. Hoffman, B.E., Grabowski, P.J. Genes Dev. (1992) [Pubmed]
  23. The U1 small nuclear ribonucleoprotein/5' splice site interaction affects U2AF65 binding to the downstream 3' splice site. Côté, J., Beaudoin, J., Tacke, R., Chabot, B. J. Biol. Chem. (1995) [Pubmed]
  24. Splicing factor SF1 from Drosophila and Caenorhabditis: presence of an N-terminal RS domain and requirement for viability. Mazroui, R., Puoti, A., Krämer, A. RNA (1999) [Pubmed]
  25. U2AF65 recruits a novel human DEAD box protein required for the U2 snRNP-branchpoint interaction. Fleckner, J., Zhang, M., Valcárcel, J., Green, M.R. Genes Dev. (1997) [Pubmed]
  26. A trans-acting factor, isolated by the three-hybrid system, that influences alternative splicing of the amyloid precursor protein minigene. Poleev, A., Hartmann, A., Stamm, S. Eur. J. Biochem. (2000) [Pubmed]
  27. Crystallization and preliminary X-ray analysis of a U2AF65 variant in complex with a polypyrimidine-tract analogue by use of protein engineering. Sickmier, E.A., Frato, K.E., Kielkopf, C.L. Acta Crystallograph. Sect. F Struct. Biol. Cryst. Commun. (2006) [Pubmed]
  28. Cotranscriptional coupling of splicing factor recruitment and precursor messenger RNA splicing in mammalian cells. Listerman, I., Sapra, A.K., Neugebauer, K.M. Nat. Struct. Mol. Biol. (2006) [Pubmed]
 
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