Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells
Genome-wide Screens Implicate Loss of Cullin Ring Ligase 3 in Persistent Proliferation and Genome Instability in TP53-Deficient Cells
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DOI：
10.1016/j.celrep.2020.03.029
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发表时间：
2020-04-07
期刊：
影响因子：
8.8
通讯作者：
Korbel, Jan O.
中科院分区：
文献类型：
--
作者：
Drainas, Alexandros P.;Lambuta, Ruxandra A.;Korbel, Jan O.
TP 53缺陷是癌症中最常见的改变;然而，仅这一点通常不足以驱动肿瘤发生。为了鉴定与TP 53缺陷相结合的促进肿瘤发生的基因，我们在同基因细胞系中进行全基因组CRISPR-Cas9敲除筛选，并结合增殖和转化测定。几种已知的肿瘤抑制因子的缺失增强了细胞增殖和转化。neddylation途径基因的缺失仅在TP 53缺陷型细胞中促进不受控制的增殖。CUL 3和TP 53的联合缺失激活由核因子κ B（NF-κ B）、AP-1和转化生长因子β（TGF-β）途径控制的致癌转录程序。该程序维持持续的细胞增殖，诱导部分上皮细胞向间充质细胞转化，并增加DNA损伤、基因组不稳定性和染色体重排。我们的发现揭示了CUL 3缺失是刺激TP 53缺陷细胞持续增殖的关键事件。这些发现可能与临床相关，因为TP 53-CUL 3缺陷细胞对共济失调毛细血管扩张突变（ATM）抑制高度敏感，暴露出可用于癌症治疗的脆弱性。
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 kappa B (NF-kappa B), AP-1, and transforming growth factor beta (TGF-beta) 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.