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Molecular and Cellular Biology, March 2005, p. 1669-1679, Vol. 25, No. 5
0270-7306/05/$08.00+0     doi:10.1128/MCB.25.5.1669-1679.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

Dap1p, a Heme-Binding Protein That Regulates the Cytochrome P450 Protein Erg11p/Cyp51p in Saccharomyces cerevisiae

Julia C. Mallory,1 Gerard Crudden,1 Ben L. Johnson,1 Caiqing Mo,2 Charles A. Pierson,2 Martin Bard,2 and Rolf J. Craven1*

Department of Molecular and Biomedical Pharmacology, Markey Cancer Center, University of Kentucky, Lexington, Kentucky,1 Department of Biology, Indiana University—Purdue University at Indianapolis, Indianapolis, Indiana2

Received 17 August 2004/ Returned for modification 4 October 2004/ Accepted 29 November 2004

Alkylating agents chemically modify DNA and cause mutations that lead to cancer. In the budding yeast Saccharomyces cerevisiae, resistance to the alkylating agent methyl methanesulfonate (MMS) is mediated in part by Dap1p (damage resistance protein 1). Dap1p is related to cytochrome b5, which activates cytochrome P450 proteins, elevating the metabolism of lipids and xenobiotic compounds. We have found that Dap1p, like cytochrome b5, binds to heme and that Dap1p targets the cytochrome P450 protein Erg11p/Cyp51p. Genetic analysis indicates that Erg11p acts downstream of Dap1p. Furthermore, Dap1p regulates the stability of Erg11p, and Erg11p is stabilized in dap1{Delta} cells by the addition of heme. Thus, Dap1p utilizes heme to stabilize Erg11p, which in turn regulates ergosterol synthesis and MMS resistance. Dap1p homologues have been identified in numerous eukaryotes, including mammals, suggesting that the Dap1p-cytochrome P450 protein pathway is broadly conserved in eukaryotic species.

* Corresponding author. Mailing address: Department of Molecular and Biomedical Pharmacology, University of Kentucky, MS-305 UKMC, Lexington, KY 40536. Phone: (859) 323-3832. Fax: (859) 257-9608. E-mail: rolf.craven{at}uky.edu.

Molecular and Cellular Biology, March 2005, p. 1669-1679, Vol. 25, No. 5
0022-538X/05/$08.00+0     doi:10.1128/MCB.25.5.1669-1679.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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