Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor
Saccharomyces cerevisiae Dap1p, a novel DNA damage response protein related to the mammalian membrane-associated progesterone receptor
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DOI：
10.1128/ec.2.2.306-317.2003
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发表时间：
2003-04-01
期刊：
影响因子：
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通讯作者：
Craven, RJ
中科院分区：
文献类型：
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作者：
Hand, RA;Jia, N;Craven, RJ
对损伤的反应对细胞存活至关重要，真核细胞需要广泛的蛋白质来进行完整的损伤反应。我们发现，在甲基化剂甲基磺酸甲酯（MMS）存在的情况下，YPL170W （DAPI[与膜相关孕酮受体相关的损伤反应蛋白]）基因是生长所必需的。DAPI开放阅读框与一个广泛保守的膜相关孕激素受体（MAPRs）家族具有同源性。DAPI的缺失导致对MMS的敏感性、端粒延长、线粒体功能丧失和部分固醇合成阻滞。dap1菌株对MMS的敏感性不是由于失去了损伤检查点。相反，在MMS处理后，dap1细胞被阻止为未出芽细胞，这表明Dap1p是损伤后细胞周期进展所必需的。Dap1p还指导对伊曲康唑和氟康唑（固醇合成抑制剂）的耐药性。我们发现dap1细胞的麦角甾醇水平略有下降，但麦角甾醇中间体角鲨烯和羊毛甾醇水平升高，表明dap1细胞在合成甾醇方面存在部分缺陷。这是将MAPR家族成员与固醇调节或损伤反应联系起来的第一个证据，这些功能可能在多种真核生物中保守。
The response to damage is crucial for cellular survival, and eukaryotic cells require a broad array of proteins for an intact damage response. We have found that the YPL170W (DAPI [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). The DAPI open reading frame shares homology with a broadly conserved family of membrane-associated progesterone receptors (MAPRs). Deletion of DAPI leads to sensitivity to MMS, elongated telomeres, loss of mitochondrial function, and partial arrest in sterol synthesis. Sensitivity of dap1 strains to MMS is not due to loss of damage checkpoints. Instead, dap1 cells are arrested as unbudded cells after MMS treatment, suggesting that Dap1p is required for cell cycle progression following damage. Dap1p also directs resistance to itraconazole and fluconazole, inhibitors of sterol synthesis. 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. This is the first evidence linking a MAPR family member to sterol regulation or the response to damage, and these functions are probably conserved in a variety of eukaryotes.