CUL3-mRNASeq

TP53 deficiency is the most common alteration in cancer but is unable to drive tumorigenesis. To identify genes promoting tumorigenesis in combination with TP53 deficiency, we performed genome-wide CRISPR/Cas9 knockout screens coupled with proliferation and transformation assays in isogenic cell lines. Loss of several known tumor suppressor genes enhanced cellular proliferation and transformation. Surprisingly, loss neddylation pathway genes, promoted uncontrolled proliferation exclusively in TP53-deficient cells. CUL3 coupled with TP53 loss results in an oncogenic transcriptional program governed by the NF?B, AP-1 and TGF-ß pathways. This program maintained persistent cellular proliferation, induced partial epithelial to mesenchymal transition, DNA damage accumulation, genomic instability, and chromosomal rearrangements. Our findings reveal CUL3 loss as a key event stimulating persistent proliferation in TP53 deficient cells. These findings may be clinically relevant, since TP53-CUL3 deficient cells are highly sensitive to ATM inhibition, exposing a vulnerability that could be exploited for cancer treatment.