Genetic interactions of G-quadruplexes in humans.
Mulhearn, Darcie S
eLife Sciences Publications Ltd
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Zyner, K. G., Mulhearn, D. S., Adhikari, S., Martínez Cuesta, S., Di Antonio, M., Erard, N., Hannon, G., et al. (2019). Genetic interactions of G-quadruplexes in humans.. eLife, 8 https://doi.org/10.7554/elife.46793
G-quadruplexes (G4) are alternative nucleic acid structures involved in transcription, translation and replication. Aberrant G4 formation and stabilisation is linked to genome instability and cancer. G4 ligand treatment disrupts key biological processes leading to cell death. To discover genes and pathways involved with G4s and gain mechanistic insights into G4 biology, we present the first unbiased genome-wide study to systematically identify human genes that promote cell death when silenced by shRNA in the presence of G4-stabilising small molecules. Many novel genetic vulnerabilities were revealed opening up new therapeutic possibilities in cancer, which we exemplified by an orthogonal pharmacological inhibition approach that phenocopies gene silencing. We find that targeting the WEE1 cell cycle kinase or USP1 deubiquitinase in combination with G4 ligand treatment enhances cell killing. We also identify new genes and pathways regulating or interacting with G4s and demonstrate that the DDX42 DEAD-box helicase is a newly discovered G4-binding protein.
Cell Line, Tumor, Cell Nucleus, Humans, Neoplasms, Neoplasm Proteins, RNA, Small Interfering, Ligands, Signal Transduction, Apoptosis, Genome, Human, Genes, Neoplasm, G-Quadruplexes, Genetic Testing
Cancer Research UK (18618)
Cancer Research UK (CB4330)
Cancer Research UK (C14303_do not transfer)
Wellcome Trust (209441/Z/17/Z)
Embargo Lift Date
External DOI: https://doi.org/10.7554/elife.46793
This record's URL: https://www.repository.cam.ac.uk/handle/1810/293993
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