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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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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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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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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DOI: https://doi.org/10.1038/ncb1733
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