title: Genetic alterations leading to increases in internal potassium concentrations are detrimental for DNA integrity in Saccharomyces cerevisiae.
abstract: We have investigated the effects of alterations in potassium homeostasis on cell cycle progression and genome stability in Saccharomyces cerevisiae. Yeast strains lacking the PPZ1 and PPZ2 phosphatase genes, which aberrantly accumulate potassium, are sensitive to agents causing replicative stress or DNA damage and present a cell cycle delay in the G(1) /S phase. A synthetic slow growth phenotype was identified in a subset of DNA repair mutants upon inhibition of Ppz activity. Moreover, we observe that this slow growth phenotype observed in cdc7(ts) mutants with reduced Ppz activity is reverted by disrupting the TRK1 potassium transporter gene. As over-expression of a mammalian potassium transporter leads to similar phenotypes, we conclude that these defects can be attributed to potassium accumulation. As we reported previously, internal potassium accumulation activates the Slt2 MAP kinase pathway. We show that the removal of SLT2 in ppz1 ppz2 mutants ameliorates sensitivity to agents causing replication stress and DNA damage, whereas over-activation of the pathway leads to similar cell cycle-related defects. Taken together, these results are consistent with inappropriate potassium accumulation reducing DNA replication efficiency, negatively influencing DNA integrity and leading to the requirement of mismatch repair, the MRX complex, or homologous recombination pathways for normal growth.
authors.affiliation: Instituto de Biología Molecular y Celular de Plantas, Universidad Politécnica de Valencia-Consejo Superior de Investigaciones Científicas, Ciudad Politécnica de Innovación, 46022 Valencia, Spain.
authors.forename: Stephanie
authors.initials: S
authors.lastname: Merchan
authors.forename: Leda
authors.initials: L
authors.lastname: Pedelini
authors.forename: Guillem
authors.initials: G
authors.lastname: Hueso
authors.forename: Arturo
authors.initials: A
authors.lastname: Calzada
authors.forename: Ramón
authors.initials: R
authors.lastname: Serrano
authors.forename: Lynne
authors.initials: L
authors.lastname: Yenush
mesh_terms: D027682:Cation Transport Proteins / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics; D004249:DNA Damage; D053843:DNA Mismatch Repair; D004261:DNA Replication / Q000187:drug effects / Q000235:genetics; D016193:G1 Phase / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics; D020928:Mitogen-Activated Protein Kinases / Q000235:genetics; D009154:Mutation / Q000235:genetics; D010749:Phosphoprotein Phosphatases / Q000235:genetics*; D011188:Potassium / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics; D016196:S Phase / Q000235:genetics; D012441:Saccharomyces cerevisiae / Q000235:genetics* / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics*
chemical_list: D027682:Cation Transport Proteins; D018797:Cell Cycle Proteins; D029701:Saccharomyces cerevisiae Proteins; C068664:TRK1 protein, S cerevisiae; C489404:CDC7 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D020928:Mitogen-Activated Protein Kinases; C072724:SLT2 protein, S cerevisiae; C075119:PPZ1 protein, S cerevisiae; C082731:PPZ2 protein, S cerevisiae; D010749:Phosphoprotein Phosphatases; D011188:Potassium