Dap1p, a heme-binding protein that regulates the cytochrome P450 protein Erg11p/Cyp51p in Saccharomyces cerevisiae

被引:79
作者
Mallory, JC
Crudden, G
Johnson, BL
Mo, CQ
Pierson, CA
Bard, M
Craven, RJ
机构
[1] Univ Kentucky, Lucille P Markey Canc Ctr, Dept Mol & Biomed Pharmacol, Lexington, KY 40536 USA
[2] Indiana Univ Purdue Univ, Dept Biol, Indianapolis, IN 46205 USA
关键词
D O I
10.1128/MCB.25.5.1669-1679.2005
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 b(5), 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 dap1Delta 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.
引用
收藏
页码:1669 / 1679
页数:11
相关论文
共 39 条
[1]   THE SAD1/RAD53 PROTEIN-KINASE CONTROLS MULTIPLE CHECKPOINTS AND DNA DAMAGE-INDUCED TRANSCRIPTION IN YEAST [J].
ALLEN, JB ;
ZHOU, Z ;
SIEDE, W ;
FRIEDBERG, EC ;
ELLEDGE, SJ .
GENES & DEVELOPMENT, 1994, 8 (20) :2401-2415
[2]   DIFFERENCES IN CRYSTAL VIOLET UPTAKE AND CATION-INDUCED DEATH AMONG YEAST STEROL MUTANTS [J].
BARD, M ;
LEES, ND ;
BURROWS, LS ;
KLEINHANS, FW .
JOURNAL OF BACTERIOLOGY, 1978, 135 (03) :1146-1148
[3]  
Begley TJ, 2002, MOL CANCER RES, V1, P103
[4]   Genes required for ionizing radiation resistance in yeast [J].
Bennett, CB ;
Lewis, LK ;
Karthikeyan, G ;
Lobachev, KS ;
Jin, YH ;
Sterling, JF ;
Snipe, JR ;
Resnick, MA .
NATURE GENETICS, 2001, 29 (04) :426-434
[5]   A genome-wide screen for methyl methanesulfonate-sensitive mutants reveals genes required for S phase progression in the presence of DNA damage [J].
Chang, M ;
Bellaoui, M ;
Boone, C ;
Brown, GW .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2002, 99 (26) :16934-16939
[6]  
Craven RJ, 2001, GENETICS, V158, P145
[7]  
Daum G, 1998, YEAST, V14, P1471, DOI 10.1002/(SICI)1097-0061(199812)14:16<1471::AID-YEA353>3.0.CO
[8]  
2-Y
[9]   Full-length cDNA sequence of a progesterone membrane-binding protein from porcine vascular smooth muscle cells [J].
Falkenstein, E ;
Meyer, C ;
Eisen, C ;
Scriba, PC ;
Wehling, M .
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, 1996, 229 (01) :86-89
[10]   The Saccharomyces repair genes at the end of the century [J].
Game, JC .
MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS, 2000, 451 (1-2) :277-293