CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation
Autor: | Yunshan Wang, Guangwei Wei, Jian-Hua Mao, Maoxiao Feng, Pengju Zhang, Huaizhi Wang, Zhongxi Zhao, Lei Bi |
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Rok vydání: | 2021 |
Předmět: |
0301 basic medicine
Genome instability Cancer Research DNA End-Joining Repair Ubiquitylation DNA Repair Carcinogenesis DNA-Activated Protein Kinase medicine.disease_cause Malignant transformation 0302 clinical medicine 2.1 Biological and endogenous factors Aetiology DNA-PKcs Cancer chemistry.chemical_classification Tumor biology Nuclear Proteins Cullin Proteins Ubiquitin ligase 030220 oncology & carcinogenesis DNA damage Clinical Sciences Oncology and Carcinogenesis Article Genomic Instability Cell Line 03 medical and health sciences Cell Line Tumor Genetics medicine Humans Oncology & Carcinogenesis Non-homologous-end joining Molecular Biology Cell Proliferation Cell Nucleus DNA ligase fungi enzymes and coenzymes (carbohydrates) 030104 developmental biology chemistry biology.protein Cancer research CUL4A Precancerous Conditions DNA Damage |
Zdroj: | Oncogene Oncogene, vol 40, iss 11 |
ISSN: | 1476-5594 0950-9232 |
Popis: | 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. |
Databáze: | OpenAIRE |
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