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Published on: July 3, 2013
Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in
Alexandros P Drainas1, Ruxandra A Lambuta1, Irina Ivanova2
1European Molecular Biology Laboratory, Genome Biology Unit, Meyerhofstr. 1, 69117 Heidelberg, Germany.
Abstract:
TP53 deficiency is the most common alteration in cancer; however, this alone is typically insufficient to drive tumorigenesis. To identify genes promoting tumorigenesis in combination with TP53 deficiency, we perform genome-wide CRISPR-Cas9 knockout screens coupled with proliferation and transformation assays in isogenic cell lines. Loss of several known tumor suppressors enhances cellular proliferation and transformation. Loss of neddylation pathway genes promotes uncontrolled proliferation exclusively in TP53-deficient cells. Combined loss of CUL3 and TP53 activates an oncogenic transcriptional program governed by the nuclear factor κB (NF-κB), AP-1, and transforming growth factor β (TGF-β) pathways. This program maintains persistent cellular proliferation, induces partial epithelial to mesenchymal transition, and increases DNA damage, 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 ataxia telangiectasia mutated (ATM) inhibition, exposing a vulnerability that could be exploited for cancer treatment.
Insights
TP53 deficiency alone rarely causes cancer. Researchers found that losing the CUL3 gene alongside TP53 deficiency drives cancer by activating specific gene pathways, offering a new therapeutic target.
Area of Science:
- Cancer Biology
- Genomics
- Molecular Oncology
Background:
- TP53 alterations are frequent in cancer but insufficient for tumorigenesis.
- Identifying cooperating genetic events with TP53 loss is crucial for understanding cancer development.
Purpose of the Study:
- To identify genes that promote tumorigenesis when TP53 is deficient.
- To elucidate the molecular mechanisms underlying TP53-deficient tumorigenesis.
Main Methods:
- Genome-wide CRISPR-Cas9 knockout screens in isogenic cell lines.
- Proliferation and transformation assays.
- Analysis of oncogenic transcriptional programs (NF-κB, AP-1, TGF-β).
Main Results:
- Loss of neddylation pathway genes, including CUL3, drives proliferation in TP53-deficient cells.
- Combined TP53 and CUL3 loss activates NF-κB, AP-1, and TGF-β pathways.
- This activation leads to persistent proliferation, partial epithelial-mesenchymal transition, and genomic instability.
Conclusions:
- CUL3 loss is a key driver of proliferation in TP53-deficient cancers.
- TP53-CUL3-deficient cells exhibit sensitivity to ATM inhibitors, suggesting a potential therapeutic strategy.
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