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
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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