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Abstract
Current approaches to define chemical-genetic interactions (CGIs) in human cell lines are resource-intensive. We designed a scalable chemical-genetic screening platform by generating a DNA damage response (DDR)-focused custom sgRNA library targeting 1011 genes with 3033 sgRNAs. We performed five proof-of-principle compound screens and found that the compounds’ known modes-of-action (MoA) were enriched among the compounds’ CGIs. These scalable screens recapitulated expected CGIs at a comparable signal-to-noise ratio (SNR) relative to genome-wide screens. Furthermore, time-resolved CGIs, captured by sequencing screens at various time points, suggested an unexpected, late interstrand-crosslinking (ICL) repair pathway response to camptothecin-induced DNA damage. Our approach can facilitate screening compounds at scale with 20-fold fewer resources than commonly used genome-wide libraries and produce biologically informative CGI profiles.
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1 University of Minnesota–Twin Cities, Department of Computer Science and Engineering, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657); University of Minnesota–Twin Cities, Bioinformatics and Computational Biology Graduate Program, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657)
2 University of Minnesota–Twin Cities, Department of Biochemistry, Molecular Biology and Biophysics, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657)
3 University of Minnesota–Twin Cities, Department of Computer Science and Engineering, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657); University of Bonn, School of Medicine and University Hospital Bonn, Institute of Human Genetics, Bonn, Germany (GRID:grid.10388.32) (ISNI:0000 0001 2240 3300)
4 University of Minnesota–Twin Cities, Bioinformatics and Computational Biology Graduate Program, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657)
5 University of Minnesota–Twin Cities, Department of Computer Science and Engineering, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657)
6 University of Toronto, Donnelly Centre, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938)
7 The Hospital for Sick Children, Program in Genetics and Genome Biology, Toronto, Canada (GRID:grid.430185.b)
8 University of Toronto, Department of Molecular Genetics, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938); The Hospital for Sick Children, Program in Genetics and Genome Biology, Toronto, Canada (GRID:grid.430185.b); University of Toronto, Institute for Biomedical Engineering, Toronto, Canada (GRID:grid.17063.33) (ISNI:0000 0001 2157 2938)
9 University of Minnesota–Twin Cities, Department of Biochemistry, Molecular Biology and Biophysics, Minneapolis, USA (GRID:grid.17635.36) (ISNI:0000 0004 1936 8657); University of Virginia, Department of Biochemistry and Molecular Genetics, Charlottesville, USA (GRID:grid.27755.32) (ISNI:0000 0000 9136 933X)