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Molecular and Cellular Biology, October 1999, p. 6608-6620, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.

DOT4 Links Silencing and Cell Growth in Saccharomyces cerevisiae

Alon Kahana1,2 and Daniel E. Gottschling1,*

Division of Basic Sciences, Fred Hutchinson Cancer Research Center, Seattle, Washington,1 and Department of Molecular Genetics and Cell Biology, The University of Chicago, Chicago, Illinois2

Received 17 May 1999/Accepted 14 June 1999

Transcriptional silencing in Saccharomyces cerevisiae occurs at specific loci and is mediated by a multiprotein complex that includes Rap1p and the Sir proteins. We studied the function of a recently identified gene, DOT4, that disrupts silencing when overexpressed. DOT4 encodes an ubiquitin processing protease (hydrolase) that is primarily located in the nucleus. By two-hybrid analysis, the amino-terminal third of Dot4p interacts with the silencing protein Sir4p. Cells lacking DOT4 exhibited reduced silencing and a corresponding decrease in the level of Sir4p. Together, these findings suggest that Dot4p regulates silencing by acting on Sir4p. In strains with several auxotrophic markers, loss of DOT4 ubiquitin hydrolase activity also results in a slow-growth defect. The defect can be partially suppressed by mutations in a subunit of the 26S proteasome, suggesting that Dot4p has the ability to prevent ubiquitin-mediated degradation. Furthermore, wild-type SIR2, SIR3, and SIR4 are required for full manifestation of the growth defect in a dot4 strain, indicating that the growth defect is caused in part by a silencing-related mechanism. We propose that Dot4p helps to restrict the location of silencing proteins to a limited set of genomic loci.

* Corresponding author. Mailing address: Fred Hutchinson Cancer Research Center, Mail Stop A3-025, 1100 Fairview Ave. North, Seattle, WA 98109. Phone: (206) 667-4494. Fax: (206) 667-5894. E-mail: dgottsch{at}fhcrc.org.

Molecular and Cellular Biology, October 1999, p. 6608-6620, Vol. 19, No. 10
0270-7306/99/$04.00+0
Copyright © 1999, American Society for Microbiology. All rights reserved.


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