Sky1 regulates the expression of sulfur metabolism genes in response to cisplatin.
Cisplatin is commonly used in cancer therapy and yeast cells are also sensitive to this compound. We present a transcriptome analysis discriminating between RNA changes induced by cisplatin treatment, which are dependent on or independent of SKY1 function--a gene whose deletion increases resistance to the drug. Gene expression changes produced by addition of cisplatin to W303 and W303-Δsky1 cells were recorded using DNA microarrays. The data, validated by quantitative PCR, revealed 122 differentially expressed genes: 69 upregulated and 53 downregulated. Among the upregulated genes, those related to sulfur metabolism were over-represented and partially dependent on Sky1. Deletions of MET4 or other genes encoding co-regulators of the expression of sulfur-metabolism-related genes, with the exception of MET28, did not modify the cisplatin sensitivity of yeast cells. One of the genes with the highest cisplatin-induced upregulation was SEO1, encoding a putative permease of sulfur compounds. We also measured the platinum, sulfur and glutathione content in W303, W303-Δsky1 and W303-Δseo1 cells after cisplatin treatment, and integration of the data suggested that these transcriptional changes might represent a cellular response that allowed chelation of cisplatin with sulfur-containing amino acids and also helped DNA repair by stimulating purine biosynthesis. The transcription pattern of stimulation of sulfur-containing amino acids and purine synthesis decreased, or even disappeared, in the W303-Δsky1 strain.
Grupo EXPRELA, Departamento de Bioloxía e Celulare Molecular, Facultade de Ciencias, Universidade da Coruña, Campus de A Coruña, 15071 A Coruña, Spain.
Silvia
S
Rodríguez-Lombardero
Grupo EXPRELA, Departamento de Bioloxía e Celulare Molecular, Facultade de Ciencias, Universidade da Coruña, Campus de A Coruña, 15071 A Coruña, Spain.
Ángel
Á
Vizoso-Vázquez
Centro Nacional de Investigaciones Oncológicas (CNIO), C/Melchor Fernández Almagro 3, 28029 Madrid, Spain.
Luis J
LJ
Lombardía
Grupo EXPRELA, Departamento de Bioloxía e Celulare Molecular, Facultade de Ciencias, Universidade da Coruña, Campus de A Coruña, 15071 A Coruña, Spain.
Manuel
M
Becerra
Grupo EXPRELA, Departamento de Bioloxía e Celulare Molecular, Facultade de Ciencias, Universidade da Coruña, Campus de A Coruña, 15071 A Coruña, Spain.
M Isabel
MI
González-Siso
Grupo EXPRELA, Departamento de Bioloxía e Celulare Molecular, Facultade de Ciencias, Universidade da Coruña, Campus de A Coruña, 15071 A Coruña, Spain.
M Esperanza
ME
Cerdán
D000970:Antineoplastic Agents / Q000494:pharmacology*; D002945:Cisplatin / Q000494:pharmacology*; D015536:Down-Regulation; D015870:Gene Expression; D020869:Gene Expression Profiling; D015966:Gene Expression Regulation, Fungal; D005978:Glutathione / Q000032:analysis / Q000378:metabolism; D020128:Inhibitory Concentration 50; D053858:Metabolic Networks and Pathways; D010984:Platinum / Q000032:analysis / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000235:genetics* / Q000378:metabolism; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology / Q000235:genetics*; D029701:Saccharomyces cerevisiae Proteins / Q000235:genetics* / Q000378:metabolism; D017384:Sequence Deletion; D013455:Sulfur / Q000032:analysis / Q000378:metabolism*; D059467:Transcriptome; D015854:Up-Regulation
D000970:Antineoplastic Agents; D029701:Saccharomyces cerevisiae Proteins; D010984:Platinum; D013455:Sulfur; C490216:SKY1 protein, S cerevisiae; D017346:Protein Serine-Threonine Kinases; D005978:Glutathione; D002945:Cisplatin