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Molecular and Cellular Biology, March 2001, p. 1997-2007, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.1997-2007.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Dosage Suppressors of pds1 Implicate Ubiquitin-Associated Domains in Checkpoint Control

Duncan J. Clarke, Guillaume Mondesert,dagger Marisa Segal, Bonnie L. Bertolaet,Dagger Sanne Jensen,§ Meira Wolff, Martha Henze, and Steven I. Reed*

Department of Molecular Biology, The Scripps Research Institute, La Jolla, California 92037

Received 1 September 2000/Returned for modification 3 October 2000/Accepted 15 December 2000

In budding yeast, anaphase initiation is controlled by ubiquitin-dependent degradation of Pds1p. Analysis of pds1 mutants implicated Pds1p in the DNA damage, spindle assembly, and S-phase checkpoints. Though some components of these pathways are known, others remain to be identified. Moreover, the essential function of Pds1p, independent of its role in checkpoint control, has not been elucidated. To identify loci that genetically interact with PDS1, we screened for dosage suppressors of a temperature-sensitive pds1 allele, pds1-128, defective for checkpoint control at the permissive temperature and essential for viability at 37°C. Genetic and functional interactions of two suppressors are described. RAD23 and DDI1 suppress the temperature and hydroxyurea, but not radiation or nocodazole, sensitivity of pds1-128. rad23 and ddi1 mutants are partially defective in S-phase checkpoint control but are proficient in DNA damage and spindle assembly checkpoints. Therefore, Rad23p and Ddi1p participate in a subset of Pds1p-dependent cell cycle controls. Both Rad23p and Ddi1p contain ubiquitin-associated (UBA) domains which are required for dosage suppression of pds1-128. UBA domains are found in several proteins involved in ubiquitin-dependent proteolysis, though no function has been assigned to them. Deletion of the UBA domains of Rad23p and Ddi1p renders cells defective in S-phase checkpoint control, implicating UBA domains in checkpoint signaling. Since Pds1p destruction, and thus checkpoint regulation of mitosis, depends on ubiquitin-dependent proteolysis, we propose that the UBA domains functionally interact with the ubiquitin system to control Pds1p degradation in response to checkpoint activation.

* Corresponding author. Mailing address: Department of Molecular Biology, The Scripps Research Institute, 10550 North Torrey Pines Rd., La Jolla, CA 92037. Phone: (858) 784-9836. Fax: (858) 784-2781. E-mail: sreed{at}scripps.edu.

dagger Present address: Sanofi-Synthelabo, Centre de Recherche de Labege, 31676 Labege, France.

Dagger Present address: Triad Therapeutics, San Diego, CA 92121.

§ Present address: National Institute for Medical Research, Division of Yeast Genetics, The Ridgeway, Mill Hill, London NW7 1AA, United Kingdom.

Molecular and Cellular Biology, March 2001, p. 1997-2007, Vol. 21, No. 6
0270-7306/01/$04.00+0   DOI: 10.1128/MCB.21.6.1997-2007.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.


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