Disease relevance of DAP1

• Cells lacking Dap1p are damage-sensitive, and we have found that inhibition of Hpr6 expression by RNA inhibition (RNAi) increases sensitivity of breast cancer cells to chemotherapeutic drugs [1].

High impact information on DAP1

• Thus, Dap1p utilizes heme to stabilize Erg11p, which in turn regulates ergosterol synthesis and MMS resistance [2].
• Dap1p is related to cytochrome b5, which activates cytochrome P450 proteins, elevating the metabolism of lipids and xenobiotic compounds [2].
• In the budding yeast Saccharomyces cerevisiae, resistance to the alkylating agent methyl methanesulfonate (MMS) is mediated in part by Dap1p (damage resistance protein 1) [2].
• The MCD spectrum confirmed this conclusion for Dap1p and indicated the axial ligand is most likely a tyrosine and not a histidine, or a cysteine; however, an aspartic acid residue could not be conclusively ruled out [3].
• We have found that the YPL170W (DAP1 [for damage response protein related to membrane-associated progesterone receptors]) gene is required for growth in the presence of the methylating agent methyl methanesulfonate (MMS) [4].

Biological context of DAP1

• The DAP1 open reading frame shares homology with a broadly conserved family of membrane-associated progesterone receptors (MAPRs) [4].
• Deletion of DAP1 leads to sensitivity to MMS, elongated telomeres, loss of mitochondrial function, and partial arrest in sterol synthesis [4].
• Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor [4].
• Instead, dap1 cells are arrested as unbudded cells after MMS treatment, suggesting that Dap1p is required for cell cycle progression following damage [4].

Associations of DAP1 with chemical compounds

• Dap1p also directs resistance to itraconazole and fluconazole, inhibitors of sterol synthesis [4].
• We have found that dap1 cells have slightly decreased levels of ergosterol but increased levels of the ergosterol intermediates squalene and lanosterol, indicating that dap1 cells have a partial defect in sterol synthesis [4].

Regulatory relationships of DAP1

• Furthermore, Dap1p regulates the stability of Erg11p, and Erg11p is stabilized in dap1Delta cells by the addition of heme [2].
• Loss of Dap1 is suppressed by elevated levels of Erg11 but not by increased heme biosynthesis [5].

Other interactions of DAP1

• Genetic analysis indicates that Erg11p acts downstream of Dap1p [2].

References