CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation

Feng, Maoxiao; Wang, Yunshan; Bi, Lei; Zhang, Pengju; Wang, Huaizhi; Zhao, Zhongxi; Mao, Jian-Hua; Wei, Guangwei

doi:10.1038/s41388-021-01690-z

CRL4A^DTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation

Journal Article · Wed Feb 24 00:00:00 EST 2021 · Oncogene

DOI:https://doi.org/10.1038/s41388-021-01690-z· OSTI ID:1816055

Feng, Maoxiao ^[1]; ^[2]; ^[3]; Zhang, Pengju ^[4]; Wang, Huaizhi ^[5]; Zhao, Zhongxi ^[6]; ^[7]; ^[8]

Shandong Univ., Jinan (China). Cheeloo College of Medicine. School of Basic Medical Sciences. Dept. of Cell Biology. Key Lab. for Experimental Teratology of the Ministry of Education; OSTI
The Second Hospital, Jinan, Shandong (China). Cheeloo College of Medicine. Dept. of Clinical Lab.; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Nanjing Univ. (China). Chinese Medicine. School of Preclinical Medicine; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Shandong Univ., Jinan (China). School of Basic Medical Science. Dept. of Biochemistry and Molecular Biology. Key Lab. Experimental Teratology of the Ministry of Education; Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Univ. of Chinese Academy of Sciences, Chongqing (China). Chongqing General Hospital. Inst. of Hepatopancreatobiliary Surgery
Shangond Univ. (China). School of Pharmaceutical Sciences
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States). Biological Systems and Engineering Division
Shandong Univ., Jinan (China). Cheeloo College of Medicine. School of Basic Medical Sciences. Dept. of Cell Biology. Key Lab. for Experimental Teratology of the Ministry of Education

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.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC)

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1816055

Journal Information:: Oncogene, Journal Name: Oncogene Journal Issue: 11 Vol. 40; ISSN 0950-9232

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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CRL4ADTL degrades DNA-PKcs to modulate NHEJ repair and induce genomic instability and subsequent malignant transformation

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