Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and identifies routes for tumour cell viability in hypoxia.
View / Open Files
Authors
Esposito, Cinzia
Morgan, Rachel E
Price, Stacey
Young, Jamie
Williams, Steven P
Maddalena, Lucas A
McDermott, Ultan
Publication Date
2021-05-21Journal Title
Communications biology
ISSN
2399-3642
Volume
4
Issue
1
Language
eng
Type
Article
This Version
VoR
Metadata
Show full item recordCitation
Thomas, L. W., Esposito, C., Morgan, R. E., Price, S., Young, J., Williams, S. P., Maddalena, L. A., et al. (2021). Genome-wide CRISPR/Cas9 deletion screen defines mitochondrial gene essentiality and identifies routes for tumour cell viability in hypoxia.. Communications biology, 4 (1) https://doi.org/10.1038/s42003-021-02098-x
Abstract
Mitochondria are typically essential for the viability of eukaryotic cells, and utilize oxygen and nutrients (e.g. glucose) to perform key metabolic functions that maintain energetic homeostasis and support proliferation. Here we provide a comprehensive functional annotation of mitochondrial genes that are essential for the viability of a large panel (625) of tumour cell lines. We perform genome-wide CRISPR/Cas9 deletion screening in normoxia-glucose, hypoxia-glucose and normoxia-galactose conditions, and identify both unique and overlapping genes whose loss influences tumour cell viability under these different metabolic conditions. We discover that loss of certain oxidative phosphorylation (OXPHOS) genes (e.g. SDHC) improves tumour cell growth in hypoxia-glucose, but reduces growth in normoxia, indicating a metabolic switch in OXPHOS gene function. Moreover, compared to normoxia-glucose, loss of genes involved in energy-consuming processes that are energetically demanding, such as translation and actin polymerization, improve cell viability under both hypoxia-glucose and normoxia-galactose. Collectively, our study defines mitochondrial gene essentiality in tumour cells, highlighting that essentiality is dependent on the metabolic environment, and identifies routes for regulating tumour cell viability in hypoxia.
Sponsorship
Wellcome Trust (RG93172)
CUH | Addenbrooke's Charitable Trust, Cambridge University Hospitals (Addenbrooke's Charitable Trust, Cambridge University Hospitals NHS Foundation Trust) (900187)
Medical Research Council (MR/K002201/2)
European Research Council (FP7/2007-2013, 319661)
Cancer Research UK (RG91141, C7358/A19442)
Identifiers
PMC8140129, 34021238
External DOI: https://doi.org/10.1038/s42003-021-02098-x
This record's URL: https://www.repository.cam.ac.uk/handle/1810/324244
Statistics
Total file downloads (since January 2020). For more information on metrics see the
IRUS guide.