title: Phosphate disruption and metal toxicity in Saccharomyces cerevisiae: effects of RAD23 and the histone chaperone HPC2.
abstract: In cells, there exists a delicate balance between accumulation of charged metal cations and abundant anionic complexes such as phosphate. When phosphate metabolism is disrupted, cell-wide spread disturbances in metal homeostasis may ensue. The best example is a yeast pho80 mutant that hyperaccumulates phosphate and as result, also hyperaccumulates metal cations from the environment and shows exquisite sensitive to toxicity from metals such as manganese. In this study, we sought to identify genes that when over-expressed would suppress the manganese toxicity of pho80 mutants. Two classes of suppressors were isolated, including the histone chaperones SPT16 and HPC2, and RAD23, a well-conserved protein involved in DNA repair and proteosomal degradation. The histone chaperone gene HPC2 reversed the elevated manganese and phosphate of pho80 mutants by specifically repressing PHO84, encoding a metal-phosphate transporter. RAD23 also reduced manganese toxicity by lowering manganese levels, but RAD23 did not alter phosphate nor repress PHO84. We observed that the RAD23-reversal of manganese toxicity reflected its role in protein quality control, not DNA repair. Our studies are consistent with a model in which Rad23p partners with the deglycosylating enzyme Png1p to reduce manganese toxicity through proteosomal degradation of glycosylated substrate(s).
authors.affiliation: Department of Environmental Health Sciences, Johns Hopkins University Bloomberg School of Public Health, Baltimore, MD, USA.
authors.forename: Leah
authors.initials: L
authors.lastname: Rosenfeld
authors.forename: Valeria C
authors.initials: VC
authors.lastname: Culotta
mesh_terms: D018797:Cell Cycle Proteins / Q000235:genetics / Q000378:metabolism*; D042002:Chromatin Assembly and Disassembly; D016213:Cyclins / Q000235:genetics; D004260:DNA Repair / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D056488:Histone Chaperones / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D008345:Manganese / Q000378:metabolism / Q000633:toxicity*; D010710:Phosphates / Q000378:metabolism*; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000378:metabolism*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D018797:Cell Cycle Proteins; D016213:Cyclins; D004268:DNA-Binding Proteins; C077306:HPC2 protein, S cerevisiae; D056488:Histone Chaperones; C066824:PHO80 protein, S cerevisiae; D010710:Phosphates; C490846:RAD23 protein, S cerevisiae; D029701:Saccharomyces cerevisiae Proteins; D014157:Transcription Factors; D008345:Manganese