Publikationsserver der Universitätsbibliothek Marburg
Titel:Identifizierung von neuen Faktoren des Gbp2-assoziierten mRNA-Exportes und den Untersuchungen an mRNA-bindenden Proteinen im Modellorganismus Saccharomyces cerevisiae.
Autor:Janning, Melanie Christiane
Weitere Beteiligte: Krebber, Heike (Prof. Dr.)
Veröffentlicht:2017
URI:https://archiv.ub.uni-marburg.de/diss/z2017/0311
DOI: https://doi.org/10.17192/z2017.0311
URN: urn:nbn:de:hebis:04-z2017-03119
DDC:610 Medizin
Titel (trans.):Identification of specific factors for the mRNA-export of Gbp2 and the examination of mRNA-binding proteins in the model organism Saccharomayces cerevisiae.
Publikationsdatum:2017-05-31
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
mRNA, Proteinsynthese, mRNA, proteinsynthesis, mRNA-Export, export

Zusammenfassung:
Die räumliche und zeitliche Trennung von RNA- und Proteinsynthese in eukaryotischen Zellen bietet eine Menge Möglichkeiten für Kontrolle und Regulation dieser Vorgänge. Gleichzeitig erfordert dies eine funktionierende Maschinerie, die den korrekten Ablauf beider Prozesse und den Transport zwischen den Kompartimenten regelt. Fehler in diesen Abläufen führen unter anderen zu neurodegenerativen Krankheiten und hämatologischen und soliden Tumoren. Viele dieser Prozesse sind hochkonserviert und konnten durch Arbeiten an dem Modellmechanismus Saccharomyces cerevisiae besser verstanden werden. In dieser Arbeit werden verschiedene, mRNA-bindende und zwischen beiden Kompartimenten pendelnde Proteine in S. cerevisiae charakterisiert. Dabei wurde unter Verwendung einer zytoplasmatischen Variante des SR-ähnlichen Proteins Gbp2 (gbp2(S15A)-GFP) nach Exportfaktoren gesucht, die den Export Gbp2 assoziierter mRNAs beeinflussen. 33 durch EMS-Mutagenese erzeugte, temperatur-sensitive Mutanten wurden untersucht. Es konnten dabei das mit dem TRAMP-Komplex assoziierte Protein Mtr4 und der Spleißingfaktor Prp8 als Faktoren identifiziert werden. GBP2 ist nicht essentiell, allerdings ist eine Überexpression von GBP2 toxisch und führt zu einer nukleären Akkumulation von poly(A)+-RNA. In dieser Arbeit konnte gezeigt werden, dass diese Toxizität unabhängig von der Lokalisation in beiden Zellkompartimenten ist, da sowohl die zytoplasmatische Variante (gbp2(S13/15/17A)) als auch das vorwiegend nukleär lokalisierte Gbp2 in Überexpression toxisch sind. Gbp2 ist daher möglicherweise bei Prozessen auf beiden Seiten der Kernmembran beteiligt. In der Tat konnten anderen Arbeiten nachweisen, dass Gbp2 im Zellkern ein wichtiger Kontrollfaktor für fehlerhaft gespleißte mRNAs ist und dass dafür die Assoziation sowohl mit Spleißingfaktoren als auch mit dem TRAMP-Komplex wichtig ist. Nab2 ist ein essentielles, mRNA-bindendes, pendelndes Protein, dass mit dem mRNA-Exportfaktor Mex67 interagiert. Der in dieser Arbeit hergestellten Mutante (nab2Δ200-249) fehlt die Bindestelle für den Importrezeptor Kap104. Diese Mutante kann einen temperatursensitiven Defekt von NAB2 (nab2-21) nicht ersetzen. Des Weiteren zeigte diese Mutante im Gegensatz zu Nab2 eine vorwiegend zytoplasmatische Lokalisation, da vermutlich der Import der Mutante durch das Fehlen der Kap104-Bindestelle eingeschränkt ist. Mittels Lokalisationsstudien dieser Nab2-Variante in verschiedenen Mutationsstämmen konnte gezeigt werden, dass der Export von nab2Δ200-249, von funktionierendem mRNA Export abhängt, allerdings ist eine Ubiquitinierung durch Tom1 für den Export von nab2Δ200-249 im Gegensatz zu Nab2 keine Voraussetzung.

Bibliographie / References

  1. Boeke, J. D., Trueheart, J., Natsoulis, G., und Fink, G. R. (1987). 5-Fluoroorotic acid as a selective agent in yeast molecular genetics. Methods in enzymology 154, 164-175.
  2. Shen, E. C., Stage-Zimmermann, T., Chui, P., und Silver, P. A. (2000). 7The yeast mRNA-binding protein Npl3p interacts with the cap-binding complex. The Journal of biological chemistry 275, 23718-23724.
  3. Gorlich, D., Henklein, P., Laskey, R. A., und Hartmann, E. (1996). A 41 amino acid motif in importin-alpha confers binding to importin-beta and hence transit into the nucleus. The EMBO journal 15, 1810-1817.
  4. Gorsch, L. C., Dockendorff, T. C., und Cole, C. N. (1995). A conditional allele of the novel repeat-containing yeast nucleoporin RAT7/NUP159 causes both rapid cessation of mRNA export and reversible clustering of nuclear pore complexes. The Journal of cell biology 129, 939-955.
  5. Weirich, C. S., Erzberger, J. P., Flick, J. S., Berger, J. M., Thorner, J., und Weis, K. (2006). Activation of the DExD/H-box protein Dbp5 by the nuclear-pore protein Gle1 and its coactivator InsP6 is required for mRNA export. Nature cell biology 8, 668-676.
  6. Liang, S., Hitomi, M., Hu, Y., Liu, Y., und Tartakoff, A. (1996a). A DEAD-box-family protein is required for nucleocytoplasmic transport of yeast mRNA. Mol Cell Biol 16, 5139-5146.
  7. Yokoyama, N., Hayashi, N., Seki, T., Pante, N., Ohba, T., Nishii, K., Kuma, K., Hayashida, T., Miyata, T., Aebi, U., und et al. (1995). A giant nucleopore protein that binds Ran/TC4. Nature 376, 184-188.
  8. Huang, Y., Yario, T. A., und Steitz, J. A. (2004a). A molecular link between SR protein dephosphorylation and mRNA export. Proceedings of the National Academy of Sciences of the United States of America 101, 9666-9670.
  9. Bossie, M. A., DeHoratius, C., Barcelo, G., und Silver, P. (1992). A mutant nuclear protein with similarity to RNA binding proteins interferes with nuclear import in yeast. Molecular biology of the cell 3, 875-893.
  10. Estruch, F. und Cole, C.N. (2003). An early function during transcription for the yeast mRNA export factor Dbp5p/Rat8p suggested by its genetic and physical interactions with transcription factor IIH components. Molecular biology of the cell 14, 1664-76.
  11. Gallardo, M., und Aguilera, A. (2001). A new hyperrecombination mutation identifies a novel yeast gene, THP1, connecting transcription elongation with mitotic recombination. Genetics 157, 79-89.
  12. Milligan, L., Torchet, C., Allmang, C., Shipman, T., und Tollervey, D. (2005). A Nuclear Surveillance Pathway for mRNAs with Defective Polyadenylation
  13. Lee, M. S., Henry, M., und Silver, P. A. (1996). A protein that shuttles between the nucleus and the cytoplasm is an important mediator of RNA export. Genes & development 10, 1233-1246.
  14. Duncan, K., Umen, J. G., und Guthrie, C. (2000). A putative ubiquitin ligase required for efficient mRNA export differentially affects hnRNP transport. Current biology : CB 10, 687-696.
  15. Birnboim, H. C., und Doly, J. (1979). A rapid alkaline extraction procedure for screening recombinant plasmid DNA. Nucleic acids research 7, 1513-1523.
  16. Shen, E. C., Henry, M. F., Weiss, V. H., Valentini, S. R., Silver, P. A., und Lee, M. S. (1998). Arginine methylation facilitates the nuclear export of hnRNP proteins. Genes & development 12, 679-691.
  17. McBride, A. E., Cook, J. T., Stemmler, E. A., Rutledge, K. L., McGrath, K. A., und Rubens, J. A. (2005). Arginine methylation of yeast mRNA-binding protein Npl3 directly affects its function, nuclear export, and intranuclear protein interactions. The Journal of biological chemistry 280, 30888-30898.
  18. Rose, M. D., Novick, P., Thomas, J. H., Botstein, D., und Fink, G. R. (1987). A Saccharomyces cerevisiae genomic plasmid bank based on a centromere-containing shuttle vector. Gene 60, 237-243.
  19. Gui, J. F., Lane, W. S., und Fu, X. D. (1994). A serine kinase regulates intracellular localization of splicing factors in the cell cycle. Nature 369, 678-682.
  20. Kalderon, D., Roberts, B. L., Richardson, W. D., und Smith, A. E. (1984). A short amino acid sequence able to specify nuclear location. Cell 39, 499-509.
  21. Caceres, J. F., Screaton, G. R., und Krainer, A. R. (1998). A specific subset of SR proteins shuttles continuously between the nucleus and the cytoplasm. Genes & development 12, 55-66.
  22. Spode, I., Maiwald, D., Hollenberg, C. P., und Suckow, M. (2002). ATF/CREB sites present in sub-telomeric regions of Saccharomyces cerevisiae chromosomes are part of promoters and act as UAS/URS of highly conserved COS genes. Journal of molecular biology 319, 407-420.
  23. Yokoya, F., Imamoto, N., Tachibana, T., und Yoneda, Y. (1999). beta-catenin can be transported into the nucleus in a Ran-unassisted manner. Molecular biology of the cell 10, 1119-1131.
  24. Bischoff, F. R., und Ponstingl, H. (1991). Catalysis of guanine nucleotide exchange on Ran by the mitotic regulator RCC1. Nature 354, 80-82.
  25. Porat, Z., Erez, O., und Kahana, C. (2006). Cellular localization and phosphorylation of Hrb1p is independent of Sky1p. Biochimica et biophysica acta 1763, 207-213.
  26. Häcker, S. (2003). Charakterisierung der SR-Proteine Npl3p, Gbp2p und Hrb1p im nukleo-cytoplasmatischen Transport., 75-77.
  27. Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature 227, 680-685.
  28. Yoshida, T., Kim, J. H., Carver, K., Su, Y., Weremowicz, S., Mulvey, L., Yamamoto, S., Brennan, C., Mei, S., Long, H., et al. (2015). CLK2 Is an Oncogenic Kinase and Splicing Regulator in Breast Cancer. Cancer research 75, 1516-1526.
  29. Bischoff, F. R., Krebber, H., Smirnova, E., Dong, W., und Ponstingl, H. (1995). Coactivation of RanGTPase and inhibition of GTP dissociation by Ran-GTP binding protein RanBP1. The EMBO journal 14, 705-715.
  30. Siebel, C. W., Feng, L., Guthrie, C., und Fu, X. D. (1999). Conservation in budding yeast of a kinase specific for SR splicing factors. Proceedings of the National Academy of Sciences of the United States of America 96, 5440-5445.
  31. Yun, C. Y., und Fu, X. D. (2000). Conserved SR protein kinase functions in nuclear import and its action is counteracted by arginine methylation in Saccharomyces cerevisiae. The Journal of cell biology 150, 707-718.
  32. Winston, F., Dollard, C., und Ricupero-Hovasse, S. L. (1995). Construction of a set of convenient Saccharomyces cerevisiae strains that are isogenic to S288C. Yeast 11, 53-55.
  33. Reichelt, R., Holzenburg, A., Buhle, E., Jr, Jarnik, M., Engel, A., und Aebi, U. (1990). Correlation between structure and mass distribution of the nuclear pore complex and of distinct pore complex components
  34. Huertas, P. und Aguilera, A. (2003). Cotranscriptionally formed DNA:RNA hybrids mediate transcription elongation impairment and transcription-associated recombination. Molecular cell 12, 711-21.
  35. Meinel, D.M. und Strasser, K. (2015). Co-transcriptional mRNP formation is coordinated within a molecular mRNP packaging station in S. cerevisiae. BioEssays : news and reviews in molecular, cellular and developmental biology 37(6), 666-77.
  36. Hurt, E., Luo, M. J., Rother, S., Reed, R., und Strasser, K. (2004). Cotranscriptional recruitment of the serine-arginine-rich (SR)-like proteins Gbp2 and Hrb1 to nascent mRNA via the TREX complex. Proceedings of the National Academy of Sciences of the United States of America 101, 1858-1862.
  37. Hammell, C. M., Gross, S., Zenklusen, D., Heath, C. V., Stutz, F., Moore, C., und Cole, C. N. (2002). Coupling of termination, 3' processing, and mRNA export. Molecular and cellular biology 22, 6441-6457.
  38. Popa, I., Harris, M. E., Donello, J. E., und Hope, T. J. (2002). CRM1-Dependent Function of a cis-Acting RNA Export Element
  39. Tieg, B., und Krebber, H. (2013). Dbp5 - from nuclear export to translation. Biochimica et biophysica acta 1829, 791-798.
  40. Hilleren, P., und Parker, R. (2001). Defects in the mRNA export factors Rat7p, Gle1p, Mex67p, and Rat8p cause hyperadenylation during 3'-end formation of nascent transcripts. Rna 7, 753-764.
  41. Carneiro, T., Carvalho, C., Braga, J., Rino, J., Milligan, L., Tollervey, D., und CarmoFonseca, M. (2007). Depletion of the yeast nuclear exosome subunit Rrp6 results in accumulation of polyadenylated RNAs in a discrete domain within the nucleolus. Molecular and cellular biology 27, 4157-4165.
  42. Hacker, S., und Krebber, H. (2004). Differential export requirements for shuttling serine/arginine-type mRNA-binding proteins. The Journal of biological chemistry 279, 5049-5052.
  43. Izaurralde, E. (2004). Directing mRNA export. Nature structural & molecular biology 11, 210-212.
  44. Serrano, P., Aubol, B. E., Keshwani, M. M., Forli, S., Ma, C. T., Dutta, S. K., Geralt, M., Wuthrich, K., und Adams, J. A. (2016). Directional Phosphorylation and Nuclear Transport of the Splicing Factor SRSF1 Is Regulated by an RNA Recognition Motif. Journal of molecular biology 428, 2430-2445.
  45. de la Cruz, J., Kressler, D., Tollervey, D., und Linder, P. (1998). Dob1p (Mtr4p) is a putative ATP-dependent RNA helicase required for the 3' end formation of 5.8S rRNA in Saccharomyces cerevisiae. The EMBO journal 17, 1128-1140.
  46. Marfatia, K. A., Crafton, E. B., Green, D. M., und Corbett, A. H. (2003). Domain analysis of the Saccharomyces cerevisiae heterogeneous nuclear ribonucleoprotein, Nab2p. Dissecting the requirements for Nab2p-facilitated poly(A) RNA export. The Journal of biological chemistry 278, 6731-6740.
  47. Hector, R. E., Nykamp, K. R., Dheur, S., Anderson, J. T., Non, P. J., Urbinati, C. R., Wilson, S. M., Minvielle-Sebastia, L., und Swanson, M. S. (2002). Dual requirement for yeast hnRNP Nab2p in mRNA poly(A) tail length control and nuclear export. The EMBO journal 21, 1800-1810.
  48. Radhakrishnan, A., Nanjappa, V., Raja, R., Sathe, G., Chavan, S., Nirujogi, R. S., Patil, A. H., Solanki, H., Renuse, S., Sahasrabuddhe, N. A., et al. (2016). Dysregulation of splicing proteins in head and neck squamous cell carcinoma. Cancer biology & therapy 17, 219-229.
  49. Ossareh-Nazari, B., Bachelerie, F., und Dargemont, C. (1997). Evidence for a Role of CRM1 in Signal-Mediated Nuclear Protein Export
  50. Dagher, S. F., und Fu, X. D. (2001). Evidence for a role of Sky1p-mediated phosphorylation in 3' splice site recognition involving both Prp8 and Prp17/Slu4. Rna 7, 1284-1297.
  51. Kohler, M., Speck, C., Christiansen, M., Bischoff, F. R., Prehn, S., Haller, H., Gorlich, D., und Hartmann, E. (1999). Evidence for distinct substrate specificities of importin alpha family members in nuclear protein import. Molecular and cellular biology 19, 7782-7791.
  52. Stade, K., Ford, C. S., Guthrie, C., und Weis, K. (1997). Exportin 1 (Crm1p) Is an Essential Nuclear Export Factor. Cell 90, 1041-1050.
  53. Kohler, A., und Hurt, E. (2007). Exporting RNA from the nucleus to the cytoplasm. Nature reviews Molecular cell biology 8, 761-773.
  54. Fornerod, M., und Ohno, M. (2002). Exportin-mediated nuclear export of proteins and ribonucleoproteins. Results and problems in cell differentiation 35, 67-91.
  55. Kutay, U., Bischoff, F. R., Kostka, S., Kraft, R., und Gorlich, D. (1997). Export of importin alpha from the nucleus is mediated by a specific nuclear transport factor. Cell 90, 1061-1071.
  56. Floch, A. G., Palancade, B., und Doye, V. (2014a). Fifty years of nuclear pores and nucleocytoplasmic transport studies: multiple tools revealing complex rules. Methods in cell biology 122, 1-40.
  57. Floch, A. G., Palancade, B., und Doye, V. (2014b). Fifyty Years of Nuclear Pore and Nucleocytoplasmic Transport Studies: Multiple Tools Revealing Complex Rules. In Nuclear Pore Complex and Nucleocytoplasmic Transport - Methods, V. Doye, ed. (Paris: Elsevier), p. 18.
  58. Wiegand, H. L., Coburn, G. A., Zeng, Y., Kang, Y., Bogerd, H. P., und Cullen, B. R. (2002). Formation of Tap/NXT1 heterodimers activates Tap-dependent nuclear mRNA export by enhancing recruitment to nuclear pore complexes. Molecular and cellular biology 22, 245-256.
  59. Allmang, C., Kufel, J., Chanfreau, G., Mitchell, P., Petfalski, E., und Tollervey, D. (1999). Functions of the exosome in rRNA, snoRNA and snRNA synthesis. The EMBO journal 18, 5399-5410.
  60. Martinez-Lumbreras, S., Taverniti, V., Zorrilla, S., Seraphin, B., und Perez-Canadillas, J. M. (2016). Gbp2 interacts with THO/TREX through a novel type of RRM domain. Nucleic acids research 44, 437-448.
  61. Sherman, F. (1981). Genetic Nomenclature. In The Molecular Biology of Yeast Saccharomyces, J.N. Strathern, E.W. Jones, und J.R. Broach, eds. (New York: Cold Spring Harbor Laboratory Press), pp. 639 - 640.
  62. Dominguez-Sanchez, M.S., Barroso, S., Gomez-Gonzalez, B., Luna, R., und Aguilera, A. (2011). Genome instability and transcription elongation impairment in human cells depleted of THO/TREX. PLoS genetics 7, e1002386.
  63. Andrade, M. A., und Bork, P. (1995). HEAT repeats in the Huntington's disease protein. Nature genetics 11, 115-116.
  64. Inoue, H., Nojima, H., und Okayama, H. (1990). High efficiency transformation of Escherichia coli with plasmids. Gene 96, 23-28.
  65. Kessler, M. M., Henry, M. F., Shen, E., Zhao, J., Gross, S., Silver, P. A., und Moore, C. L. (1997). Hrp1, a sequence-specific RNA-binding protein that shuttles between the nucleus and the cytoplasm, is required for mRNA 3'-end formation in yeast. Genes & development 11, 2545-2556.
  66. Cheng, H., Dufu, K., Lee, C. S., Hsu, J. L., Dias, A., und Reed, R. (2006). Human mRNA export machinery recruited to the 5' end of mRNA. Cell 127, 1389-1400.
  67. Koffa, M. D., Casanova, C. M., Santarella, R., Kocher, T., Wilm, M., und Mattaj, I. W. (2006). HURP is part of a Ran-dependent complex involved in spindle formation. Current biology : CB 16, 743-754.
  68. Kutay, U., Lipowsky, G., Izaurralde, E., Bischoff, F. R., Schwarzmaier, P., Hartmann, E., und Gorlich, D. (1998). Identification of a tRNA-Specific Nuclear Export Receptor. Molecular cell 1, 359-369.
  69. Enenkel, C., Blobel, G., und Rexach, M. (1995). Identification of a Yeast Karyopherin Heterodimer That Targets Import Substrate to Mammalian Nuclear Pore Complexes 10.1074/jbc.270.28.16499. J Biol Chem 270, 16499-16502.
  70. Windgassen, M., und Krebber, H. (2003). Identification of Gbp2 as a novel poly(A)+ RNA-binding protein involved in the cytoplasmic delivery of messenger RNAs in yeast. EMBO reports 4, 278-283.
  71. Lee, C. G., Hague, L. K., Li, H., und Donnelly, R. (2004). Identification of toposome, a novel multisubunit complex containing topoisomerase IIalpha. Cell Cycle 3, 638- 647.
  72. Tsukihashi, Y., Miyake, T., Kawaichi, M., und Kokubo, T. (2000). Impaired Core Promoter Recognition Caused by Novel Yeast TAF145 Mutations Can Be Restored by Creating a Canonical TATA Element within the Promoter Region of the TUB2 Gene
  73. Jakel, S., und Gorlich, D. (1998). Importin beta, transportin, RanBP5 and RanBP7 mediate nuclear import of ribosomal proteins in mammalian cells. The EMBO journal 17, 4491-4502.
  74. Neuhoff, V., Arold, N., Taube, D., und Ehrhardt, W. (1988). Improved staining of proteins in polyacrylamide gels including isoelectric focusing gels with clear background at nanogram sensitivity using Coomassie Brilliant Blue G-250 and R250. Electrophoresis 9, 255-262.
  75. Pasquinelli, A. E., Powers, M. A., Lund, E., Forbes, D., und Dahlberg, J. E. (1997). Inhibition of mRNA export in vertebrate cells by nuclear export signal conjugates. Proceedings of the National Academy of Sciences of the United States of America 94, 14394-14399.
  76. Alcazar-Roman, A. R., Tran, E. J., Guo, S., und Wente, S. R. (2006). Inositol hexakisphosphate and Gle1 activate the DEAD-box protein Dbp5 for nuclear mRNA export. Nature cell biology 8, 711-716.
  77. Lei, E. P., und Silver, P. A. (2002). Intron status and 3'-end formation control cotranscriptional export of mRNA. Genes & development 16, 2761-2766.
  78. Amberg, D. C., Goldstein, A. L., und Cole, C. N. (1992). Isolation and characterization of RAT1: an essential gene of Saccharomyces cerevisiae required for the efficient nucleocytoplasmic trafficking of mRNA. Genes & development 6, 1173-1189.
  79. Clarke, L., und Carbon, J. (1980). Isolation of a yeast centromere and construction of functional small circular chromosomes. Nature 287, 504-509.
  80. Rout, M. P., und Blobel, G. (1993). Isolation of the yeast nuclear pore complex. The Journal of cell biology 123, 771-783.
  81. 11 16 Aitchison, J. D., Blobel, G., und Rout, M. P. (1996). Kap104p: a karyopherin involved in the nuclear transport of messenger RNA binding proteins. Science 274, 624-627.
  82. Lee, D. C. Y., und Aitchison, J. D. (1999b). Kap104p-mediated Nuclear Import. NUCLEAR LOCALIZATION SIGNALS IN mRNA-BINDING PROTEINS AND THE ROLE OF RAN AND RNA
  83. Lee, D. C., und Aitchison, J. D. (1999a). Kap104p-mediated nuclear import. Nuclear localization signals in mRNA-binding proteins and the role of Ran and Rna. The Journal of biological chemistry 274, 29031-29037.
  84. Conti, E., Muller, C. W., und Stewart, M. (2006). Karyopherin flexibility in nucleocytoplasmic transport. Curr Opin Struct Biol 16, 237-244.
  85. Bachmann, B. J. (1983). Linkage map of Escherichia coli K-12, edition 7. Microbiological reviews 47, 180-230.
  86. Holmes, R. K., Tuck, A. C., Zhu, C., Dunn-Davies, H. R., Kudla, G., Clauder-Munster, S., Granneman, S., Steinmetz, L. M., Guthrie, C., und Tollervey, D. (2015). Loss of the Yeast SR Protein Npl3 Alters Gene Expression Due to Transcription Readthrough. PLoS genetics 11, e1005735.
  87. Eckner, R., Ellmeier, W., und Birnstiel, M. L. (1991). Mature mRNA 3' end formation stimulates RNA export from the nucleus. The EMBO journal 10, 3513-3522.
  88. Pemberton, L. F., und Paschal, B. M. (2005). Mechanisms of receptor-mediated nuclear import and nuclear export. Traffic 6, 187-198.
  89. Lei, E. P., Krebber, H., und Silver, P. A. (2001). Messenger RNAs are recruited for nuclear export during transcription. Genes & development 15, 1771-1782.
  90. Segref, A., Sharma, K., Doye, V., Hellwig, A., Huber, J., Luhrmann, R., und Hurt, E. (1997). Mex67p, a novel factor for nuclear mRNA export, binds to both poly(A)+ RNA and nuclear pores. The EMBO journal 16, 3256-3271.
  91. Schwartz, T. U. (2005). Modularity within the architecture of the nuclear pore complex. Current Opinion in Structural Biology
  92. Cingolani, G., Bednenko, J., Gillespie, M. T., und Gerace, L. (2002). Molecular basis for the recognition of a nonclassical nuclear localization signal by importin beta. Molecular cell 10, 1345-1353.
  93. Sambrook, J., Fritsch, E. F., und Maniatis, T. (1989). Molecular Cloning: a laboratory manual., (New York: Cold Spring Harbor Laboratory Press,).
  94. Stewart, M. (2007a). Molecular mechanism of the nuclear protein import cycle. Nature reviews Molecular cell biology 8, 195-208.
  95. Baierlein, C., Hackmann, A., Gross, T., Henker, L., Hinz, F., und Krebber, H. (2013). Monosome formation during translation initiation requires the serine/arginine-rich protein Npl3. Molecular and cellular biology 33, 4811-4823.
  96. Senger, B., Simos, G., Bischoff, F. R., Podtelejnikov, A., Mann, M., und Hurt, E. (1998). Mtr10p functions as a nuclear import receptor for the mRNA-binding protein Npl3p. The EMBO journal 17, 2196-2207.
  97. Sanford, J. R., Longman, D., und Caceres, J. F. (2003). Multiple roles of the SR protein family in splicing regulation. Prog Mol Subcell Biol 31, 33-58.
  98. Mitchell, P., und Tollervey, D. (2000). Musing on the structural organization of the exosome complex. Nat Struct Biol 7, 843-846.
  99. Anderson, J. T., Wilson, S. M., Datar, K. V., und Swanson, M. S. (1993). NAB2: a yeast nuclear polyadenylated RNA-binding protein essential for cell viability. Molecular and cellular biology 13, 2730-2741.
  100. Gallardo, M., Luna, R., Erdjument-Bromage, H., Tempst, P., und Aguilera, A. (2003). Nab2p and the Thp1p-Sac3p complex functionally interact at the interface between transcription and mRNA metabolism. The Journal of biological chemistry 278, 24225-24232.
  101. Green, D. M., Marfatia, K. A., Crafton, E. B., Zhang, X., Cheng, X., und Corbett, A. H. (2002a). Nab2p is required for poly(A) RNA export in Saccharomyces cerevisiae and is regulated by arginine methylation via Hmt1p. The Journal of biological chemistry 277, 7752-7760.
  102. la Cour, T., Gupta, R., Rapacki, K., Skriver, K., Poulsen, F. M., und Brunak, S. (2003). NESbase version 1.0: a database of nuclear export signals
  103. Ho, J. H.-N., Kallstrom, G., und Johnson, A. W. (2000). Nmd3p Is a Crm1p-dependent Adapter Protein for Nuclear Export of the Large Ribosomal Subunit 10.1083/jcb.151.5.1057. J Cell Biol 151, 1057-1066.
  104. Kerscher, O., Hieter, P., Winey, M., und Basrai, M. A. (2001). Novel role for a Saccharomyces cerevisiae nucleoporin, Nup170p, in chromosome segregation. Genetics 157, 1543-1553.
  105. Ribbeck, K., Lipowsky, G., Kent, H. M., Stewart, M., und Gorlich, D. (1998). NTF2 mediates nuclear import of Ran. The EMBO journal 17, 6587-6598.
  106. Gadal, O., Strau{beta}, D., Kessl, J., Trumpower, B., Tollervey, D., und Hurt, E. (2001). Nuclear Export of 60S Ribosomal Subunits Depends on Xpo1p and Requires a Nuclear Export Sequence-Containing Factor, Nmd3p, That Associates with the Large Subunit Protein Rpl10p
  107. Suntharalingam, M., Alcazar-Roman, A. R., und Wente, S. R. (2004). Nuclear export of the yeast mRNA-binding protein Nab2 is linked to a direct interaction with Gfd1 and to Gle1 function. The Journal of biological chemistry 279, 35384-35391.
  108. Fagotto, F., Gluck, U., und Gumbiner, B. M. (1998). Nuclear localization signalindependent and importin/karyopherin-independent nuclear import of beta-catenin. Current biology : CB 8, 181-190.
  109. Santos-Rosa, H., Moreno, H., Simos, G., Segref, A., Fahrenkrog, B., Pante, N., und Hurt, E. (1998). Nuclear mRNA export requires complex formation between Mex67p and Mtr2p at the nuclear pores. Molecular and cellular biology 18, 6826- 6838.
  110. Beck, M., Forster, F., Ecke, M., Plitzko, J. M., Melchior, F., Gerisch, G., Baumeister, W., und Medalia, O. (2004). Nuclear pore complex structure and dynamics revealed by cryoelectron tomography. Science 306, 1387-1390.
  111. Galy, V., Gadal, O., Fromont-Racine, M., Romano, A., Jacquier, A., und Nehrbass, U. (2004). Nuclear retention of unspliced mRNAs in yeast is mediated by perinuclear Mlp1. Cell 116, 63-73.
  112. Cullen, B. R. (2003). Nuclear RNA export. Journal of cell science 116, 587-597.
  113. Anderson, J. T., und Wang, X. (2009). Nuclear RNA surveillance: no sign of substrates tailing off. Critical reviews in biochemistry and molecular biology 44, 16-24.
  114. Truant, R., Fridell, R. A., Benson, E. R., Herold, A., und Cullen, B. R. (1998). Nucleocytoplasmic shuttling by protein nuclear import factors. Eur J Cell Biol 77, 269-275.
  115. Fried, H., und Kutay, U. (2003). Nucleocytoplasmic transport: taking an inventory. Cellular and molecular life sciences : CMLS 60, 1659-1688.
  116. Paulillo, S. M., Phillips, E. M., Koser, J., Sauder, U., Ullman, K. S., Powers, M. A., und Fahrenkrog, B. (2005). Nucleoporin domain topology is linked to the transport status of the nuclear pore complex. Journal of molecular biology 351, 784-798.
  117. Ribbeck, K., Groen, A. C., Santarella, R., Bohnsack, M. T., Raemaekers, T., Kocher, T., Gentzel, M., Gorlich, D., Wilm, M., Carmeliet, G., et al. (2006). NuSAP, a mitotic RanGTP target that stabilizes and cross-links microtubules. Molecular biology of the cell 17, 2646-2660.
  118. Herold, A., Klymenko, T., und Izaurralde, E. (2001). NXF1/p15 heterodimers are essential for mRNA nuclear export in Drosophila. Rna 7, 1768-1780.
  119. Vinciguerra, P., Iglesias, N., Camblong, J., Zenklusen, D., und Stutz, F. (2005). Perinuclear Mlp proteins downregulate gene expression in response to a defect in mRNA export. The EMBO journal 24, 813-823.
  120. Gilbert, W., Siebel, C. W., und Guthrie, C. (2001). Phosphorylation by Sky1p promotes Npl3p shuttling and mRNA dissociation. Rna 7, 302-313.
  121. Thyagarajan, A., Strong, M. J., und Szaro, B. G. (2007). Post-transcriptional control of neurofilaments in development and disease. Exp Cell Res 313, 2088-2097.
  122. Saiki, R. K., Gelfand, D. H., Stoffel, S., Scharf, S. J., Higuchi, R., Horn, G. T., Mullis, K. B., und Erlich, H. A. (1988). Primer-directed enzymatic amplification of DNA with a thermostable DNA polymerase. Science 239, 487-491.
  123. Grainger, R. J., und Beggs, J. D. (2005). Prp8 protein: at the heart of the spliceosome. Rna 11, 533-557.
  124. Hackmann, A., Wu, H., Schneider, U. M., Meyer, K., Jung, K., und Krebber, H. (2014). Quality control of spliced mRNAs requires the shuttling SR proteins Gbp2 and Hrb1. Nature communications 5, 3123.
  125. Hodge, C.A., Colot, H.V., Stafford, P. und Cole, C.N. (1999) Rat8p/Dbp5p is a shuttling transport factor that interacts with Rat7p/Nup159p and Gle1p and suppresses the mRNA export defect of xpo1-1 cells. The EMBO journal 18, 5778- 88.
  126. Stewart, M. (2007b). Ratcheting mRNA out of the nucleus. Molecular cell 25, 327-330.
  127. Kelly, S. M., Pabit, S. A., Kitchen, C. M., Guo, P., Marfatia, K. A., Murphy, T. J., Corbett, A. H., und Berland, K. M. (2007). Recognition of polyadenosine RNA by zinc finger proteins. Proceedings of the National Academy of Sciences of the United States of America 104, 12306-12311.
  128. Masuda, S., Das, R., Cheng, H., Hurt, E., Dorman, N., und Reed, R. (2005). Recruitment of the human TREX complex to mRNA during splicing. Genes & development 19, 1512-1517.
  129. Weis, K. (2003). Regulating access to the genome: nucleocytoplasmic transport throughout the cell cycle. Cell 112, 441-451.
  130. Iglesias, N., und Stutz, F. (2008). Regulation of mRNP dynamics along the export pathway. FEBS letters 582, 1987-1996.
  131. Chlebowski, A., Lubas, M., Jensen, T. H., und Dziembowski, A. (2013). RNA decay machines: the exosome. Biochimica et biophysica acta 1829, 552-560.
  132. Huang, Y., und Carmichael, G. G. (1996). Role of polyadenylation in nucleocytoplasmic transport of mRNA. Molecular and cellular biology 16, 1534- 1542.
  133. Schmid, M., Poulsen, M. B., Olszewski, P., Pelechano, V., Saguez, C., Gupta, I., Steinmetz, L. M., Moore, C., und Jensen, T. H. (2012). Rrp6p controls mRNA poly(A) tail length and its decoration with poly(A) binding proteins. Molecular cell 47, 267-280.
  134. Huber, J., Cronshagen, U., Kadokura, M., Marshallsay, C., Wada, T., Sekine, M., und Luhrmann, R. (1998). Snurportin1, an m3G-cap-specific nuclear import receptor with a novel domain structure. The EMBO journal 17, 4114-4126.
  135. Graveley, B. R. (2000). Sorting out the complexity of SR protein functions. Rna 6, 1197-1211.
  136. Strasser, K., und Hurt, E. (2001). Splicing factor Sub2p is required for nuclear mRNA export through its interaction with Yra1p. Nature 413, 648-652.
  137. da Silva, M. R., Moreira, G. A., Goncalves da Silva, R. A., de Almeida Alves Barbosa, E., Pais Siqueira, R., Teixera, R. R., Almeida, M. R., Silva Junior, A., Fietto, J. L., und Bressan, G. C. (2015). Splicing Regulators and Their Roles in Cancer Biology and Therapy. BioMed research international 2015, 150514.
  138. Wang, H. Y., Lin, W., Dyck, J. A., Yeakley, J. M., Songyang, Z., Cantley, L. C., und Fu, X. D. (1998). SRPK2: a differentially expressed SR protein-specific kinase involved in mediating the interaction and localization of pre-mRNA splicing factors in mammalian cells. The Journal of cell biology 140, 737-750.
  139. Huang, Y., und Steitz, J. A. (2005). SRprises along a messenger's journey. Molecular cell 17, 613-615.
  140. Komeno, Y., Huang, Y. J., Qiu, J., Lin, L., Xu, Y., Zhou, Y., Chen, L., Monterroza, D. D., Li, H., DeKelver, R. C., et al. (2015). SRSF2 Is Essential for Hematopoiesis, and Its Myelodysplastic Syndrome-Related Mutations Dysregulate Alternative PremRNA Splicing. Molecular and cellular biology 35, 3071-3082.
  141. Huang, Y., Gattoni, R., Stevenin, J., und Steitz, J. A. (2003). SR splicing factors serve as adapter proteins for TAP-dependent mRNA export. Molecular cell 11, 837-843.
  142. Kuersten, S., Arts, G.-J., Walther, T. C., Englmeier, L., und Mattaj, I. W. (2002). Steady-State Nuclear Localization of Exportin-t Involves RanGTP Binding and Two Distinct Nuclear Pore Complex Interaction Domains
  143. Lukasiewicz, R., Velazquez-Dones, A., Huynh, N., Hagopian, J., Fu, X. D., Adams, J., und Ghosh, G. (2007). Structurally unique yeast and mammalian serine-arginine protein kinases catalyze evolutionarily conserved phosphorylation reactions. The Journal of biological chemistry 282, 23036-23043.
  144. Shuman, S. (2001). Structure, mechanism, and evolution of the mRNA capping apparatus. Progress in nucleic acid research and molecular biology 66, 1-40.
  145. Cingolani, G., Petosa, C., Weis, K., und Muller, C. W. (1999). Structure of importinbeta bound to the IBB domain of importin-alpha. Nature 399, 221-229.
  146. Grant, R. P., Marshall, N. J., Yang, J. C., Fasken, M. B., Kelly, S. M., Harreman, M. T., Neuhaus, D., Corbett, A. H., und Stewart, M. (2008). Structure of the N-terminal Mlp1-binding domain of the Saccharomyces cerevisiae mRNA-binding protein, Nab2. Journal of molecular biology 376, 1048-1059.
  147. Rodriguez-Navarro, S., Fischer, T., Luo, M. J., Antunez, O., Brettschneider, S., Lechner, J., Perez-Ortin, J. E., Reed, R., und Hurt, E. (2004). Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery. Cell 116, 75-86.
  148. Gruter, P., Tabernero, C., von Kobbe, C., Schmitt, C., Saavedra, C., Bachi, A., Wilm, M., Felber, B. K., und Izaurralde, E. (1998). TAP, the human homolog of Mex67p, mediates CTE-dependent RNA export from the nucleus. Molecular cell 1, 649-659.
  149. Truant, R., und Cullen, B. R. (1999). The Arginine-Rich Domains Present in Human Immunodeficiency Virus Type 1 Tat and Rev Function as Direct Importin beta - Dependent Nuclear Localization Signals. Mol Cell Biol 19, 1210-1217.
  150. Colwill, K., Pawson, T., Andrews, B., Prasad, J., Manley, J. L., Bell, J. C., und Duncan, P. I. (1996). The Clk/Sty protein kinase phosphorylates SR splicing factors and regulates their intranuclear distribution. The EMBO journal 15, 265-275.
  151. Tran, E. J., Zhou, Y., Corbett, A. H., und Wente, S. R. (2007). The DEAD-box protein Dbp5 controls mRNA export by triggering specific RNA:protein remodeling events. Molecular cell 28, 850-859.
  152. Lund, M. K., und Guthrie, C. (2005). The DEAD-box protein Dbp5p is required to dissociate Mex67p from exported mRNPs at the nuclear rim. Molecular cell 20, 645- 651.
  153. Gross, T., Siepmann, A., Sturm, D., Windgassen, M., Scarcelli, J. J., Seedorf, M., Cole, C. N., und Krebber, H. (2007). The DEAD-box RNA helicase Dbp5 functions in translation termination. Science 315, 646-649.
  154. Nachury, M. V., und Weis, K. (1999). The direction of transport through the nuclear pore can be inverted. Proceedings of the National Academy of Sciences of the United States of America 96, 9622-9627.
  155. Dworetzky, S. I., Lanford, R. E., und Feldherr, C. M. (1988). The effects of variations in the number and sequence of targeting signals on nuclear uptake. The Journal of cell biology 107, 1279-1287.
  156. Le Hir, H., Gatfield, D., Izaurralde, E., und Moore, M. J. (2001). The exon-exon junction complex provides a binding platform for factors involved in mRNA export and nonsense-mediated mRNA decay. The EMBO journal 20, 4987-4997.
  157. Gilbert, W., und Guthrie, C. (2004). The Glc7p nuclear phosphatase promotes mRNA export by facilitating association of Mex67p with mRNA. Molecular cell 13, 201- 212.
  158. Moore, M. S., und Blobel, G. (1993). The GTP-binding protein Ran/TC4 is required for protein import into the nucleus. Nature 365, 661-663.
  159. Jakel, S., Albig, W., Kutay, U., Bischoff, F. R., Schwamborn, K., Doenecke, D., und Gorlich, D. (1999). The importin beta/importin 7 heterodimer is a functional nuclear import receptor for histone H1. The EMBO journal 18, 2411-2423.
  160. Minvielle-Sebastia, L., Preker, P. J., Wiederkehr, T., Strahm, Y., und Keller, W. (1997). The major yeast poly(A)-binding protein is associated with cleavage factor IA and functions in premessenger RNA 3'-end formation. Proceedings of the National Academy of Sciences of the United States of America 94, 7897-7902.
  161. Houseley, J., und Tollervey, D. (2009). The many pathways of RNA degradation. Cell 136, 763-776.
  162. Hackmann, A., Gross, T., Baierlein, C., und Krebber, H. (2011). The mRNA export factor Npl3 mediates the nuclear export of large ribosomal subunits. EMBO reports 12, 1024-1031.
  163. Fischer, T., Strasser, K., Racz, A., Rodriguez-Navarro, S., Oppizzi, M., Ihrig, P., Lechner, J., und Hurt, E. (2002). The mRNA export machinery requires the novel Sac3p-Thp1p complex to dock at the nucleoplasmic entrance of the nuclear pores. The EMBO journal 21, 5843-5852.
  164. Weirich, C.S., Erzberger, J.P., Berger, J.M. und Weis, K. (2004) The N-terminal domain of Nup159 forms a beta-propeller that functions in mRNA export by tethering the helicase Dbp5 to the nuclear pore. Molecular cell 16, 749-60.
  165. Akhtar, A., und Gasser, S. M. (2007). The nuclear envelope and transcriptional control. Nature reviews Genetics 8, 507-517.
  166. Roth, K. M., Wolf, M. K., Rossi, M., und Butler, J. S. (2005). The nuclear exosome contributes to autogenous control of NAB2 mRNA levels. Molecular and cellular biology 25, 1577-1585.
  167. Schmid, M., Olszewski, P., Pelechano, V., Gupta, I., Steinmetz, L. M., und Jensen, T. H. (2015). The Nuclear PolyA-Binding Protein Nab2p Is Essential for mRNA Production. Cell reports 12, 128-139.
  168. Wente, S. R., und Rout, M. P. (2010). The nuclear pore complex and nuclear transport. Cold Spring Harbor perspectives in biology 2, a000562.
  169. Strambio-De-Castillia, C., Niepel, M., und Rout, M. P. (2010). The nuclear pore complex: bridging nuclear transport and gene regulation. Nature reviews Molecular cell biology 11, 490-501.
  170. Fahrenkrog, B., und Aebi, U. (2003). The nuclear pore complex: nucleocytoplasmic transport and beyond. Nature reviews Molecular cell biology 4, 757-766.
  171. Lim, R. Y., und Fahrenkrog, B. (2006). The nuclear pore complex up close. Current opinion in cell biology 18, 342-347.
  172. Del Priore, V., Snay, C. A., Bahr, A., und Cole, C. N. (1996). The product of the Saccharomyces cerevisiae RSS1 gene, identified as a high-copy suppressor of the rat7-1 temperature-sensitive allele of the RAT7/NUP159 nucleoporin, is required for efficient mRNA export. Molecular biology of the cell 7, 1601-1621.
  173. Howard, J. M., und Sanford, J. R. (2015). The RNAissance family: SR proteins as multifaceted regulators of gene expression. Wiley interdisciplinary reviews RNA 6, 93-110.
  174. Lewis, J. D., und Izaurralde, E. (1997). The role of the cap structure in RNA processing and nuclear export. European journal of biochemistry / FEBS 247, 461-469.
  175. Michlewski, G., Sanford, J. R., und Caceres, J. F. (2008). The splicing factor SF2/ASF regulates translation initiation by enhancing phosphorylation of 4E-BP1. Molecular cell 30, 179-189.
  176. Yoh, S. M., Cho, H., Pickle, L., Evans, R. M., und Jones, K. A. (2007). The Spt6 SH2 domain binds Ser2-P RNAPII to direct Iws1-dependent mRNA splicing and export. Genes & development 21, 160-174.
  177. Rougemaille, M., Dieppois, G., Kisseleva-Romanova, E., Gudipati, R. K., Lemoine, S., Blugeon, C., Boulay, J., Jensen, T. H., Stutz, F., Devaux, F., und Libri, D. (2008). THO/Sub2p functions to coordinate 3'-end processing with gene-nuclear pore association. Cell 135, 308-321.
  178. Sahebi, M., Hanafi, M. M., van Wijnen, A. J., Azizi, P., Abiri, R., Ashkani, S., und Taheri, S. (2016). Towards understanding pre-mRNA splicing mechanisms and the role of SR proteins. Gene 587, 107-119.
  179. Gorlich, D., und Kutay, U. (1999). TRANSPORT BETWEEN THE CELL NUCLEUS AND THE CYTOPLASM
  180. Siomi, M. C., Eder, P. S., Kataoka, N., Wan, L., Liu, Q., und Dreyfuss, G. (1997). Transportin-mediated Nuclear Import of Heterogeneous Nuclear RNP Proteins 10.1083/jcb.138.6.1181. J Cell Biol 138, 1181-1192.
  181. Nakielny, S., Siomi, M. C., Siomi, H., Michael, W. M., Pollard, V., und Dreyfuss, G. (1996). Transportin: Nuclear Transport Receptor of a Novel Nuclear Protein Import Pathway. Experimental Cell Research 229, 261-266.
  182. Macara, I. G. (2001). Transport into and out of the nucleus. Microbiology and molecular biology reviews : MMBR 65, 570-594, table of contents.
  183. Iglesias, N., Tutucci, E., Gwizdek, C., Vinciguerra, P., Von Dach, E., Corbett, A. H., Dargemont, C., und Stutz, F. (2010). Ubiquitin-mediated mRNP dynamics and surveillance prior to budding yeast mRNA export. Genes & development 24, 1927- 1938.
  184. Krebber, H., Taura, T., Lee, M. S., und Silver, P. A. (1999). Uncoupling of the hnRNP Npl3p from mRNAs during the stress-induced block in mRNA export. Genes & development 13, 1994-2004.
  185. Fischer, T., Rodriguez-Navarro, S., Pereira, G., Racz, A., Schiebel, E., und Hurt, E. (2004). Yeast centrin Cdc31 is linked to the nuclear mRNA export machinery. Nature cell biology 6, 840-848.
  186. Hellmuth, K., Lau, D. M., Bischoff, F. R., Kunzler, M., Hurt, E., und Simos, G. (1998). Yeast Los1p Has Properties of an Exportin-Like Nucleocytoplasmic Transport Factor for tRNA. Mol Cell Biol 18, 6374-6386.
  187. Dunn, E. F., Hammell, C. M., Hodge, C. A., und Cole, C. N. (2005). Yeast poly(A)- binding protein, Pab1, and PAN, a poly(A) nuclease complex recruited by Pab1, connect mRNA biogenesis to export. Genes & development 19, 90-103.
  188. Windgassen, M., Sturm, D., Cajigas, I. J., Gonzalez, C. I., Seedorf, M., Bastians, H., und Krebber, H. (2004). Yeast shuttling SR proteins Npl3p, Gbp2p, and Hrb1p are part of the translating mRNPs, and Npl3p can function as a translational repressor. Molecular and cellular biology 24, 10479-10491.
  189. Strasser, K., und Hurt, E. (2000). Yra1p, a conserved nuclear RNA-binding protein, interacts directly with Mex67p and is required for mRNA export. The EMBO journal 19, 410-420.

* Das Dokument ist im Internet frei zugänglich - Hinweise zu den Nutzungsrechten
© UB Marburg 1997 - 2024 Universitätsbibliothek Marburg