Paraquat, a herbicide linked to Parkinson's disease, generates reactive oxygen species (ROS), which causes cell death. Because the source of paraquat-induced ROS production remains unknown, we conducted a CRISPR-based positive-selection screen to identify metabolic genes essential for paraquat-induced cell death. Our screen uncovered three genes, POR (cytochrome P450 oxidoreductase), ATP7A (copper transporter), and SLC45A4 (sucrose transporter), required for paraquat–induced cell death. Furthermore, our results revealed POR as the source of paraquat-induced ROS production. Thus, our study highlights the use of functional genomic screens for uncovering redox biology.
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We thank the Genome Technology Core of the Whitehead Institute for deep sequencing the genomic DNA samples. We thank the Flow Cytometry Core of Northwestern University for providing the BD LSRFortessa cell analyzer to assess cell viability. We are grateful to M.P. Murphy (University of Cambridge) for providing us MitoParaquat. This work was supported by a National Institute of Aging grant (5P01AG049665) to N.S.C. C.R.R. was supported by a National Institutes of Health postdoctoral training grant (T32 HL076139-11). H.K. was supported by a National Institutes of Health pre-doctoral training grant (T32 CA9560-30). K.B. was supported by grants from the National Institutes of Health (K22 CA1936600), a Searle Scholar Award, an Irma T. Hirschl/Monique Weill–Caulier Trust Award, and the Sidney Kimmel Foundation. D.M.S. is an investigator of the Howard Hughes Medical Institute.
The authors declare no competing financial interests.
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Reczek, C., Birsoy, K., Kong, H. et al. A CRISPR screen identifies a pathway required for paraquat-induced cell death. Nat Chem Biol 13, 1274–1279 (2017). https://doi.org/10.1038/nchembio.2499
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