Genome-wide in vivo CRISPR screens identify GATOR1 as a TP53 induced tumour suppressor

bioRxiv (Cold Spring Harbor Laboratory)(2022)

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摘要
Abstract The tumour suppressor TP53 (called TRP53 in mice) protects cells from neoplastic transformation by activating diverse cellular processes 1,2 . While tumour suppression by TRP53-mediated induction of apoptosis, cell cycle arrest, cell senescence and DNA repair has been well characterised 1-4 , there is so far no example of the loss of a TP53 activated regulator of cellular metabolism promoting tumour development. Using in vivo genome-wide CRISPR knockout screens we identified Nprl3 and Depdc5 , encoding components of the GATOR1 complex which inhibits mTORC1, as novel tumour suppressors that inhibit c-MYC-driven lymphomagenesis. In a parallel in vivo CRISPR knockout screen using a focused library of sgRNAs targeting TRP53 binding sites in gene promoters/enhancers, we discovered that loss of a TRP53 binding site in the Nprl3 promoter accelerated c-MYC-driven lymphomagenesis to a similar extent as loss of the Nprl3 gene itself. These findings along with the observations that (i) Nprl3 is upregulated in response to DNA damaging drugs in wild-type (wt) but not TRP53 knockout cells and that (ii) GATOR1 deficient Eμ-Myc lymphomas all retained wt TRP53 function, whereas ∼30% of control Eμ-Myc lymphomas had selected for mutations in Trp53 , suggested that direct transcriptional inducton of GATOR1 by TRP53 is a critical tumour suppressive mechanism. Additionally, we found that GATOR1 deficient tumours exhibited abnormally increased mTORC1 signalling, which rendered them highly sensitive to the mTORC1 inhibitor rapamycin, both in vitro and in vivo . Collectively, these findings identify the first mechanism by which TRP53 suppresses tumourigenesis by transcriptional activation of a regulator of metabolism and they also reveal a potential bio-marker to predict responses to mTORC1 inhibitors in the clinic.
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crispr screens,tp53,gator1,tumour suppressor,genome-wide
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