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Yeast Ataxin-7 links histone deubiquitination with gene gating and mRNA export

Nature Cell Biology volume 10, pages 707–715 (2008)Cite this article

Abstract

Targeting of a gene to the nuclear pore complexes (NPCs), known as gene gating, can affect its transcriptional state1,2,3,4,5,6,7,8,9. However, the mechanism underlying gene gating is poorly understood. Here, we have identified SAGA-associated Sgf73 (ref. 10), the yeast orthologue of human Ataxin-7 (ref. 11), as a regulator of histone H2B ubiquitin levels, a modification linked to both transcription initiation and elongation12,13. Sgf73 is a key component of a minimal histone-deubiquitinating complex. Activation of the H2B deubiquitinating protease, Ubp8, is cooperative and requires complex formation with the amino-terminal zinc-finger-containing domain of Sgf73 and Sgf11–Sus1. Through a separate domain, Sgf73 mediates recruitment of the TREX-2 mRNA export factors Sac3 and Thp1 to SAGA and their stable interaction with Sus1–Cdc31. This latter step is crucial to target TREX-2 to the NPC. Loss of Sgf73 from SAGA abrogates gene gating of GAL1 and causes a GAL1 mRNA export defect. Thus, Sgf73 provides a molecular scaffold to integrate the regulation of H2B ubiquitin levels, tethering of a gene to the NPC and export of mRNA.

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Figure 1: Sgf73 anchors Ubp8 to SAGA.
Figure 2: An N-terminal domain of Sgf73 regulates Ubp8 activity.
Figure 3: Sgf73 affects the integrity of the TREX-2 mRNA export complex.
Figure 4: Sgf73 and Sus1 affect targeting of Sac3 and Thp1 to the NPC.
Figure 5: Sgf73 is required for GAL1 gene gating and mRNA export.

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References

  1. Akhtar, A. & Gasser, S. M. The nuclear envelope and transcriptional control. Nature Rev. Genet. 8, 507–517 (2007).

    Article  CAS  Google Scholar 

  2. Brickner, J. H. & Walter, P. Gene recruitment of the activated INO1 locus to the nuclear membrane. PLoS Biol. 2, e342 (2004).

    Article  Google Scholar 

  3. Cabal, G. G. et al. SAGA interacting factors confine sub-diffusion of transcribed genes to the nuclear envelope. Nature 441, 770–773 (2006).

    Article  CAS  Google Scholar 

  4. Casolari, J. M. et al. Genome-wide localization of the nuclear transport machinery couples transcriptional status and nuclear organization. Cell 117, 427–439 (2004).

    Article  CAS  Google Scholar 

  5. Dieppois, G., Iglesias, N. & Stutz, F. Cotranscriptional recruitment to the mRNA export receptor Mex67p contributes to nuclear pore anchoring of activated genes. Mol. Cell Biol. 26, 7858–7870 (2006).

    Article  CAS  Google Scholar 

  6. Drubin, D. A., Garakani, A. M. & Silver, P. A. Motion as a phenotype: the use of live-cell imaging and machine visual screening to characterize transcription-dependent chromosome dynamics. BMC Cell Biol. 7, 19 (2006).

    Article  Google Scholar 

  7. Taddei, A. et al. Nuclear pore association confers optimal expression levels for an inducible yeast gene. Nature 441, 774–778 (2006).

    Article  CAS  Google Scholar 

  8. Abruzzi, K. C., Belostotsky, D. A., Chekanova, J. A., Dower, K. & Rosbash, M. 3´-end formation signals modulate the association of genes with the nuclear periphery as well as mRNP dot formation. EMBO J. 25, 4253–4262 (2006).

    Article  CAS  Google Scholar 

  9. Dilworth, D. J. et al. The mobile nucleoporin Nup2p and chromatin-bound Prp20p function in endogenous NPC-mediated transcriptional control. J. Cell Biol. 171, 955–965 (2005).

    Article  CAS  Google Scholar 

  10. McMahon, S. J., Pray-Grant, M. G., Schieltz, D., Yates, J. R., 3rd & Grant, P. A. Polyglutamine-expanded spinocerebellar ataxia-7 protein disrupts normal SAGA and SLIK histone acetyltransferase activity. Proc. Natl Acad. Sci. USA 102, 8478–8482 (2005).

    Article  CAS  Google Scholar 

  11. Helmlinger, D. et al. Ataxin-7 is a subunit of GCN5 histone acetyltransferase-containing complexes. Hum. Mol. Genet. 13, 1257–1265 (2004).

    Article  CAS  Google Scholar 

  12. Henry, K. W. et al. Transcriptional activation via sequential histone H2B ubiquitylation and deubiquitylation, mediated by SAGA-associated Ubp8. Genes Dev. 17, 2648–2663 (2003).

    Article  CAS  Google Scholar 

  13. Pavri, R. et al. Histone H2B monoubiquitination functions cooperatively with FACT to regulate elongation by RNA polymerase II. Cell 125, 703–717 (2006).

    Article  CAS  Google Scholar 

  14. Daniel, J. A. & Grant, P. A. Multi-tasking on chromatin with the SAGA coactivator complexes. Mutat. Res. 618, 135–148 (2007).

    Article  CAS  Google Scholar 

  15. Rodriguez-Navarro, S. et al. Sus1, a functional component of the SAGA histone acetylase complex and the nuclear pore-associated mRNA export machinery. Cell 116, 75–86 (2004).

    Article  CAS  Google Scholar 

  16. Fischer, T. et al. Yeast centrin Cdc31 is linked to the nuclear mRNA export machinery. Nature Cell Biol. 6, 840–848 (2004).

    Article  CAS  Google Scholar 

  17. Fischer, T. et al. The mRNA export machinery requires the novel Sac3p-Thp1p complex to dock at the nucleoplasmic entrance of the nuclear pores. EMBO J. 21, 5843–5852 (2002).

    Article  CAS  Google Scholar 

  18. Ingvarsdottir, K. et al. H2B ubiquitin protease Ubp8 and Sgf11 constitute a discrete functional module within the Saccharomyces cerevisiae SAGA complex. Mol. Cell Biol. 25, 1162–1172 (2005).

    Article  CAS  Google Scholar 

  19. Lee, K. K., Florens, L., Swanson, S. K., Washburn, M. P. & Workman, J. L. The deubiquitylation activity of Ubp8 is dependent upon Sgf11 and its association with the SAGA complex. Mol. Cell Biol. 25, 1173–1182 (2005).

    Article  CAS  Google Scholar 

  20. Köhler, A. et al. The mRNA export factor Sus1 is involved in Spt/Ada/Gcn5 acetyltransferase-mediated H2B deubiquitinylation through its interaction with Ubp8 and Sgf11. Mol. Biol. Cell 17, 4228–4236 (2006).

    Article  Google Scholar 

  21. Shukla, A., Stanojevic, N., Duan, Z., Sen, P. & Bhaumik, S. R. Ubp8p, a histone deubiquitinase whose association with SAGA is mediated by Sgf11p, differentially regulates lysine 4 methylation of histone H3 in vivo. Mol. Cell Biol. 26, 3339–3352 (2006).

    Article  CAS  Google Scholar 

  22. Tanny, J. C., Erdjument-Bromage, H., Tempst, P. & Allis, C. D. Ubiquitylation of histone H2B controls RNA polymerase II transcription elongation independently of histone H3 methylation. Genes Dev. 21, 835–847 (2007).

    Article  CAS  Google Scholar 

  23. Kao, C. F. et al. Rad6 plays a role in transcriptional activation through ubiquitylation of histone H2B. Genes Dev. 18, 184–195 (2004).

    Article  CAS  Google Scholar 

  24. Xiao, T. et al. Histone H2B ubiquitylation is associated with elongating RNA polymerase II. Mol. Cell Biol. 25, 637–651 (2005).

    Article  CAS  Google Scholar 

  25. Wyce, A. et al. H2B ubiquitylation acts as a barrier to Ctk1 nucleosomal recruitment prior to removal by Ubp8 within a SAGA-related complex. Mol. Cell 27, 275–288 (2007).

    Article  CAS  Google Scholar 

  26. Daniel, J. A. et al. Deubiquitination of histone H2B by a yeast acetyltransferase complex regulates transcription. J. Biol. Chem. 279, 1867–1871 (2004).

    Article  CAS  Google Scholar 

  27. Govind, C. K., Zhang, F., Qiu, H., Hofmeyer, K. & Hinnebusch, A. G. Gcn5 promotes acetylation, eviction and methylation of nucleosomes in transcribed coding regions. Mol. Cell 25, 31–42 (2007).

    Article  CAS  Google Scholar 

  28. Bryant, G. O. & Ptashne, M. Independent recruitment in vivo by gal4 of two complexes required for transcription. Mol. Cell 11, 1301–1309 (2003).

    Article  CAS  Google Scholar 

  29. Larschan, E. & Winston, F. The S. cerevisiae SAGA complex functions in vivo as a coactivator for transcriptional activation by Gal4. Genes Dev. 15, 1946–1956 (2001).

    Article  CAS  Google Scholar 

  30. Palhan, V. B. et al. Polyglutamine-expanded ataxin-7 inhibits STAGA histone acetyltransferase activity to produce retinal degeneration. Proc. Natl Acad. Sci. USA 102, 8472–8477 (2005).

    Article  CAS  Google Scholar 

  31. Shukla, A., Bajwa, P. & Bhaumik, S. R. SAGA-associated Sgf73p facilitates formation of the preinitiation complex assembly at the promoters either in a HAT-dependent or independent manner in vivo. Nucleic Acids Res. 34, 6225–6232 (2006).

    Article  CAS  Google Scholar 

  32. Dang, L. C., Melandri, F. D. & Stein, R. L. Kinetic and mechanistic studies on the hydrolysis of ubiquitin C-terminal 7-amido-4-methylcoumarin by deubiquitinating enzymes. Biochemistry 37, 1868–1879 (1998).

    Article  CAS  Google Scholar 

  33. Helmlinger, D., Tora, L. & Devys, D. Transcriptional alterations and chromatin remodeling in polyglutamine diseases. Trends Genet. 22, 562–570 (2006).

    Article  CAS  Google Scholar 

  34. Rigaut, G. et al. A generic protein purification method for protein complex characterization and proteome exploration. Nature Biotech. 17, 1030–1032 (1999).

    Article  CAS  Google Scholar 

  35. Kao, C. F. & Osley, M. A. In vivo assays to study histone ubiquitylation. Methods 31, 59–66 (2003).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank Sabine Merker, Petra Ihrig and J. Lechner for performing mass spectrometry; Heiner Sähr for technical assitance and Silke Hauf (Max-Planck-Institut, Tübingen), Suzanne Elsasser, Dan Finley (Harvard Medical School, Boston) and Dieter Kressler for comments on the mansucript. We thank Mary Ann Osley for yeast strains and Catherine Dargemont for the GAL1 RNA probe. E.H. is a recipient of grants from the Deutsche Forschungsgemeinschaft (Leibniz Programme, SFB 638/B3) and Fonds der Chemischen Industrie. G.G.C. is a recipient of a fellowship from the Association pour la Researche sur le Cancer (ARC).

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Authors and Affiliations

  1. Biochemie-Zentrum der Universität Heidelberg, Im Neuenheimer Feld 328, Heidelberg, 69120, Germany

    Alwin Köhler, Maren Schneider & Ed Hurt

  2. Universitätskinderklinik Heidelberg, Im Neuenheimer Feld 151, Heidelberg, 69120, Germany

    Alwin Köhler

  3. Unité de Biologie Cellulaire du Noyau, Institut Pasteur, 25 rue du Dr Roux, Paris cedex 15, 75724, France

    Ghislain G. Cabal & Ulf Nehrbass

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Contributions

A.K. and E.H. designed the project; A.K. and M.S. performed the experiments; G.G.C. conducted the gene gating assay (Fig. 5a) and was supervised by U.N.; A.K. and E.H. wrote the manuscript and all authors commented on the manuscript.

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Correspondence to Ed Hurt.

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Supplementary Figures S1, S2, S3, S4 and Supplementary Table 1 (PDF 1062 kb)

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Köhler, A., Schneider, M., Cabal, G. et al. Yeast Ataxin-7 links histone deubiquitination with gene gating and mRNA export. Nat Cell Biol 10, 707–715 (2008). https://doi.org/10.1038/ncb1733

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