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.
Original language | English (US) |
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Article number | 2508 |
Journal | Scientific reports |
Volume | 14 |
Issue number | 1 |
DOIs | |
State | Published - Dec 2024 |
Bibliographical note
Publisher Copyright:© 2024, The Author(s).
PubMed: MeSH publication types
- Journal Article