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Eukaryotic Cell, October 2003, p. 962-970, Vol. 2, No. 5
1535-9778/03/$08.00+0     DOI: 10.1128/EC.2.5.962-970.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Ask10p Mediates the Oxidative Stress-Induced Destruction of the Saccharomyces cerevisiae C-Type Cyclin Ume3p/Srb11p

Todd J. Cohen,1 Kun Lee,2 Lisa H. Rutkowski,2 and Randy Strich2*

Department of Molecular Biology, Duke University Medical Center, Durham, North Carolina 27710,1 Program for Cell and Developmental Biology, Fox Chase Cancer Center, Philadelphia, Pennsylvania 191112

Received 15 May 2003/ Accepted 29 July 2003

Srb11p-Srb10p is the budding yeast C-type cyclin-cyclin-dependent kinase that is required for the repression of several stress response genes. To relieve this repression, Srb11p is destroyed in cells exposed to stressors, including heat shock and oxidative stress. In the present study, we identified Ask10p (for activator of Skn7) by two-hybrid analysis as an interactor with Srb11p. Coimmunoprecipitation studies confirmed this association, and we found that, similar to Srb11p-Srb10p, Ask10p is a component of the RNA polymerase II holoenzyme. Ask10p is required for Srb11p destruction in response to oxidative stress but not heat shock. Moreover, this destruction is important since the hypersensitivity of an ask10 mutant strain to oxidative stress is rescued by deleting SRB11. We further show that Ask10p is phosphorylated in response to oxidative stress but not heat shock. This modification requires the redundant mitogen-activated protein (MAP) kinase kinase Mkk1/2 but not their normal MAP kinase target Slt2p. Moreover, the other vegetative MAP kinases—Hog1p, Fus3p, or Kss1p—are not required for Ask10p phosphorylation, suggesting the existence of an alternative pathway for transducing the Pkc1p->Bck1->Mkk1/2 oxidative stress signal. In conclusion, Ask10p is a new component of the RNA polymerase II holoenzyme and an important regulator of the oxidative stress response. In addition, these results define a new role for the Pkc1p MAP kinase cascade (except the MAP kinase itself) in transducing the oxidative damage signal directly to the RNA polymerase II holoenzyme, thereby bypassing the stress-activated transcription factors.

* Corresponding author. Mailing address: Program for Cell and Developmental Biology, Fox Chase Cancer Center, 7701 Burholme Ave., Philadelphia, PA 19111. Phone: (215) 728-5321. Fax: (215) 379-5715. E-mail: r_Strich{at}fccc.edu.

Eukaryotic Cell, October 2003, p. 962-970, Vol. 2, No. 5
1535-9778/03/$08.00+0     DOI: 10.1128/EC.2.5.962-970.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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