Gene

Cell biology

Cell metabolism

Biology

Peroxisome

Reactive oxygen species

Gene knockout

Endocrinology

Metabolism

Biochemistry

Evolutionary biology

Genetics

Mitochondrial DNA

Organic chemistry

Oxygen

Energy metabolism

Mitochondrion

Lipid metabolism

Chemistry

Cell

Genetic screen

Phenotype

<h2>Summary</h2> Human cells are able to sense and adapt to variations in oxygen levels. Historically, much research in this field has focused on hypoxia-inducible factor (HIF) signaling and reactive oxygen species (ROS). Here, we perform genome-wide CRISPR growth screens at 21%, 5%, and 1% oxygen to systematically identify gene knockouts with relative fitness defects in high oxygen (213 genes) or low oxygen (109 genes), most without known connection to HIF or ROS. Knockouts of many mitochondrial pathways thought to be essential, including complex I and enzymes in Fe-S biosynthesis, grow relatively well at low oxygen and thus are buffered by hypoxia. In contrast, in certain cell types, knockout of lipid biosynthetic and peroxisomal genes causes fitness defects only in low oxygen. Our resource nominates genetic diseases whose severity may be modulated by oxygen and links hundreds of genes to oxygen homeostasis.

Genetic Screen for Cell Fitness in High or Low Oxygen Highlights Mitochondrial and Lipid Metabolism