CRL4A(DTL) degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation.
CRL4A(DTL) degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation.
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CRL4A(DTL) 降解 DNA-PKcs 以调节 NHEJ 修复并诱导基因组不稳定和随后的恶性转化
DOI：
10.1038/s41388-021-01690-z
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发表时间：
2021-03
期刊：
影响因子：
8
通讯作者：
Wei G
中科院分区：
文献类型：
--
作者：
Feng M;Wang Y;Bi L;Zhang P;Wang H;Zhao Z;Mao JH;Wei G
DNA损伤和DNA损伤修复不当引起的基因组不稳定性是导致恶性转化和肿瘤发生的主要原因之一。DNA双链断裂（DSB）是DNA损伤的最有害形式，非同源末端连接（NHEJ）机制在启动DSB修复中起主导和优先作用。据报道，一种研究充分的癌基因，泛素连接酶Cullin 4A（CUL 4A），被招募到基因组DNA中的DSB位点，但它是否调节DSB修复的NHEJ机制尚不清楚。在这里，我们发现CUL 4A-DTL连接酶复合物靶向NHEJ修复途径中的DNA-PKcs蛋白，用于核降解。CUL 4A或DTL的过表达降低了NHEJ修复效率，随后增加了DSB的积累。此外，我们证明了在正常细胞中CUL 4A或DTL的过表达导致基因组不稳定和恶性增殖。与体外研究结果一致，在人癌前病变中，CUL 4A表达随恶性程度的增加而逐渐增加，并与DNA-PKcs表达呈负相关，与γ-H2 AX表达呈正相关。总的来说，这项研究提供了强有力的证据表明，CUL 4A-DTL轴增加基因组不稳定性，并通过抑制NHEJ修复增强正常细胞的后续恶性转化。这些结果也提示CUL 4A可能是癌前病变的预后标志物和潜在的癌症治疗靶点。
Genomic instability induced by DNA damage and improper DNA damage repair is one of the main causes of malignant transformation and tumorigenesis. DNA double strand breaks (DSBs) are the most detrimental form of DNA damage, and nonhomologous end-joining (NHEJ) mechanisms play dominant and priority roles in initiating DSB repair. A well-studied oncogene, the ubiquitin ligase Cullin 4A (CUL4A), is reported to be recruited to DSB sites in genomic DNA, but whether it regulates NHEJ mechanisms of DSB repair is unclear. Here, we discovered that the CUL4A-DTL ligase complex targeted the DNA-PKcs protein in the NHEJ repair pathway for nuclear degradation. Overexpression of either CUL4A or DTL reduced NHEJ repair efficiency and subsequently increased the accumulation of DSBs. Moreover, we demonstrated that overexpression of either CUL4A or DTL in normal cells led to genomic instability and malignant proliferation. Consistent with the in vitro findings, in human precancerous lesions, CUL4A expression gradually increased with increasing malignant tendency and was negatively correlated with DNA-PKcs and positively correlated with γ-H2AX expression. Collectively, this study provided strong evidence that the CUL4A-DTL axis increases genomic instability and enhances the subsequent malignant transformation of normal cells by inhibiting NHEJ repair. These results also suggested that CUL4A may be a prognostic marker of precancerous lesions and a potential therapeutic target in cancer.
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