Research ResourceMOLECULAR BIOLOGY

Quantitative genetic screening reveals a Ragulator-FLCN feedback loop that regulates the mTORC1 pathway

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Science Signaling  15 Sep 2020:
Vol. 13, Issue 649, eaba5665
DOI: 10.1126/scisignal.aba5665

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Perturb and observe screening in haploid cells

Yeast have been a powerful model organism for genetic screens because they can easily be genetically manipulated during the haploid portion of their life cycle. De Zan et al. used a quantitative genetic screen in the HAP1 haploid human cell line that generated reproducible results in different laboratories without explicit standardization. The authors used this screening approach to identify genes whose loss of function by mutation increased or decreased the phosphorylation of ribosomal protein S6 (RPS6), a measure of the activity of mTORC1, a complex that mediates responses to nutrient availability. Adding pharmacological or genetic perturbations to the screen showed that LAMTOR4 enhanced the inhibition of mTORC1 by rapamycin, an effect not demonstrated by the related LAMTOR5, and that LAMTOR4 had a synthetic sick/lethal interaction with folliculin. This approach has the potential to reveal regulators of signaling pathways that function in specific contexts.

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