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A putative stimulatory role for activator turnover in gene expression


The ubiquitin–proteasome system (UPS) promotes the destruction of target proteins by attaching to them a ubiquitin chain that is recognized by the 26S proteasome1. The UPS influences most cellular processes, and its targets include transcriptional activators that are primary determinants of gene expression. Emerging evidence indicates that non-proteolytic functions of the UPS might stimulate transcriptional activity2,3. Here we show that the proteolysis of some transcriptional activators by the UPS can stimulate their function. We focused on the role of UPS-dependent proteolysis in the function of inducible transcriptional activators in yeast, and found that inhibition of the proteasome4 reduced transcription of the targets of the activators Gcn4, Gal4 and Ino2/4. In addition, mutations in SCFCdc4, the ubiquitin ligase for Gcn4 (ref. 5), or mutations in ubiquitin that prevent degradation6, also impaired the transcription of Gcn4 targets. These transcriptional defects were manifested despite the enhanced abundance of Gcn4 on cognate promoters. Proteasome inhibition also decreased the association of RNA polymerase II with Gcn4, Gal4 and Ino2/4 targets, as did mutations in SCFCdc4 for Gcn4 targets. Expression of a stable phospho-site mutant of Gcn4 (ref. 7) or disruption of the kinases that target Gcn4 for turnover5,7 alleviated the sensitivity of Gcn4 activity to defects in the UPS.

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Figure 1: UPS-dependent proteolysis positively regulates inducible transcriptional activators.
Figure 2: Defects in the UPS lead to the accumulation of ubiquitinated Gcn4 and impair the association of RNA polymerase II with Gcn4 and Gal4 targets.
Figure 3: The UPS has little effect on the activity of stable, non-phosphorylated versions of Gcn4.


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We thank D. Finley, D. H. Wolf, R. Young, A. Hinnebusch, J. Shaw, B. Westermann, J. Nunnari and G. Braus for gifts of strains and reagents; B. Tansey for communicating results before publication; and J. Shaw, B. Westermann, J. Nunnari, S. Sadis, A. Ansari and the members of the Deshaies laboratory for comments and criticism. This work was supported in part by an NIH Research Project Grant to R.J.D. R.J.D. is an Investigator of the Howard Hughes Medical Institute. J.R.L. was supported by an NIH National Research Service Award and a Caltech-Amgen Postdoctoral Fellowship.

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Correspondence to Raymond J. Deshaies.

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Supplementary information

Supplementary Notes

This file contains Supplementary Table 1 and 2, Supplementary Figure Legends, Supplementary Methods, and Supplementary Discussion. This file also contains details of NIH support. (DOC 166 kb)

Supplementary Figure 1

Proteasome inhibition represses the transcription of many Gcn4 targets and of INO1, a target of the transcriptional activators, Ino2 and Ino4. (PDF 36 kb)

Supplementary Figure 2

Gal4-TAP functions similarly to wild-type Gal4. pdr5δ, GAL4-TAP strains were treated as in Fig. 1b. (PDF 29 kb)

Supplementary Figure 3

Proteasome inhibition does not affect the dynamic association of Gal80 with a Gal4 target. (PDF 29 kb)

Supplementary Figure 4

Gcn4 is required for the association of RNA polymerase II (polII) with HIS4. (PDF 16 kb)

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Lipford, J., Smith, G., Chi, Y. et al. A putative stimulatory role for activator turnover in gene expression. Nature 438, 113–116 (2005).

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