Sensitivity to nitrogen mustard in Saccharomyces cerevisiae is independently determined by regulated choline permease and DNA repair.
Sensitivity of yeast cells to the bifunctional alkylating agent nitrogen mustard (HN2) depends on two independently operating physiological mechanisms of cellular metabolism: dynamics of uptake of HN2 via choline permease, encoded in the gene HNM1/CTR, and repair of HN2-induced DNA damage. Uptake of choline and HN2 is impaired in mutant alleles of HNM1/CTR, leading to a HN2 hyper-resistant phenotype. Overexpression of HNM1/CTR leads to HN2 sensitivity higher than that of the wild type. While mutation and regulation of HNM1/CTR have pronounced effects on the cell's HN2 sensitivity, they do not interfere with repair of HN2-induced DNA damage, a process whose quality independently determines a yeast cell's sensitivity to HN2. Consequently, HNM1/CTR overexpression in an excision repair-deficient strain leads to extreme HN2 sensitivity whereas a mutational block of HNM1/CTR, in combination with excision proficiency, yields a HN2 hyper-resistant phenotype.
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Institut für Mikrobiologie der J.W. Goethe-Universität, Frankfurt/Main, Germany.
Brendel
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D001692:Biological Transport; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D002794:Choline / Q000378:metabolism; D004260:DNA Repair / Q000502:physiology*; D004271:DNA, Fungal / Q000502:physiology*; D005656:Fungal Proteins / Q000502:physiology*; D015966:Gene Expression Regulation, Fungal / Q000502:physiology; D007294:Inositol / Q000378:metabolism; D008466:Mechlorethamine / Q000378:metabolism / Q000494:pharmacology*; D026901:Membrane Transport Proteins; D009154:Mutation / Q000502:physiology; D011401:Promoter Regions, Genetic; D012441:Saccharomyces cerevisiae / Q000187:drug effects* / Q000502:physiology
D002352:Carrier Proteins; D004271:DNA, Fungal; D005656:Fungal Proteins; D026901:Membrane Transport Proteins; C065637:choline transporter; D007294:Inositol; D008466:Mechlorethamine; D002794:Choline