Superfund Research Program
Comparative and Functional Genomics Analysis of Superfund Toxicants
Project Leader: Paul Russell (The Scripps Research Institute)
Grant Number: P42ES010337
Funding Period: 2000-2017
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This project uses the fission yeast Schizosaccharomyces pombe to provide a comprehensive understanding of the genes and biochemical pathways that determine cellular resistance to toxic metals and metalloids such as arsenic, cadmium and chromium. Using global fitness profiling by barcode sequencing, the research team identified 180 genes required for arsenic or cadmium resistance, with a highly significant overlap of 36 genes. A subset of these genes account for almost all proteins required for incorporating sulfur into the cysteine-rich glutathione and phytochelatin peptides that chelate cadmium and arsenic. Ubiquinone, siroheme, and pyridoxal 5'-phosphate biosynthesis were also identified as critical for Cd/As tolerance. Notable differences are apparent with corresponding screens in the budding yeast Saccharomyces cerevisiae, underscoring the utility of analyzing toxic metal defense mechanisms in both organisms. One pattern to emerge from these studies is that DNA repair and DNA damage checkpoint genes are particularly important for cellular resistance to chromium but not arsenic or cadmium. The Mre11-Rad50-Nbs1 (MRN) protein complex, which is a “first-responder” to double-strand breaks, is particularly critical in cells exposed to chromium. A flow cytometry-based competitive growth assay has been adopted to quantify heavy metal toxicity with exceptional sensitivity, precision and reproducibility.