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Molecular Pharmacology

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Research ArticleArticle

Genomic Screening in Vivo Reveals the Role Played by Vacuolar H+ ATPase and Cytosolic Acidification in Sensitivity to DNA-Damaging Agents Such as Cisplatin

Chunyan Liao, Bin Hu, Matthew J. Arno and Barry Panaretou
Molecular Pharmacology February 2007, 71 (2) 416-425; DOI: https://doi.org/10.1124/mol.106.030494
Chunyan Liao
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Bin Hu
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Matthew J. Arno
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Barry Panaretou
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Abstract

Screening the Saccharomyces cerevisiae homozygous diploid deletion library against a sublethal concentration of cisplatin revealed 76 strains sensitive to the drug. As expected, the largest category of deletions, representing 40% of the sensitive strains, was composed of strains lacking genes involved in DNA replication and damage repair. Deletions lacking function of the highly conserved vacuolar H+ translocating ATPase (V-ATPase) composed the category representing the second largest number of sensitive strains. The effect on cell death exhibited by V-ATPase mutants was found to be a general response to various DNA damaging agents as opposed to being specific to cisplatin, as evidenced by sensitivity of the mutants to hydroxyurea (a DNA-alkylating agent) and UV irradiation. Loss of V-ATPase does not affect DNA repair, because double mutants defective for V-ATPase function and DNA repair pathways were more sensitive to cisplatin than the single mutants. V-ATPase mutants are more prone to DNA damage than wild-type cells, indicated by enhanced activation of the DNA damage checkpoint. Vacuole function per se is not cisplatin-sensitive, because vacuolar morphology and vacuolar acidification were unaffected by cisplatin in wild-type cells. V-ATPase also controls cytoplasmic pH, so the enhanced sensitivity to DNA damage may be associated with the drop in pHi associated with V-ATPase mutants. The increased loss in cell viability induced by cisplatin at lower pH in V-ATPase mutants supports this hypothesis. The loss in viability seen in wild-type cells under the same conditions was far less dramatic.

Footnotes

  • This work was funded by grants from the Royal Society (to B.P.) and the Biotechnology and Biological Sciences Research Council (to B.H.).

  • ABBREVIATIONS: NER, nucleotide excision repair; RER, recombination dependent repair; PR, postreplication repair; RR, replication-dependent repair; V-ATPase, vacuolar H+-transporting ATPase; YPD, yeast extract/peptone/dextrose; PBS, phosphate-buffered saline; HU, hydroxyurea; MMS, methyl methanesulfonate.

    • Received September 21, 2006.
    • Accepted November 8, 2006.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 71 (2)
Molecular Pharmacology
Vol. 71, Issue 2
1 Feb 2007
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Research ArticleArticle

Genomic Screening in Vivo Reveals the Role Played by Vacuolar H+ ATPase and Cytosolic Acidification in Sensitivity to DNA-Damaging Agents Such as Cisplatin

Chunyan Liao, Bin Hu, Matthew J. Arno and Barry Panaretou
Molecular Pharmacology February 1, 2007, 71 (2) 416-425; DOI: https://doi.org/10.1124/mol.106.030494

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Research ArticleArticle

Genomic Screening in Vivo Reveals the Role Played by Vacuolar H+ ATPase and Cytosolic Acidification in Sensitivity to DNA-Damaging Agents Such as Cisplatin

Chunyan Liao, Bin Hu, Matthew J. Arno and Barry Panaretou
Molecular Pharmacology February 1, 2007, 71 (2) 416-425; DOI: https://doi.org/10.1124/mol.106.030494
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