PMID- 33627782
OWN - NLM
STAT- MEDLINE
DCOM- 20211014
LR  - 20230129
IS  - 1476-5594 (Electronic)
IS  - 0950-9232 (Print)
IS  - 0950-9232 (Linking)
VI  - 40
IP  - 11
DP  - 2021 Mar
TI  - CRL4A(DTL) degrades DNA-PKcs to modulate NHEJ repair and induce genomic 
      instability and subsequent malignant transformation.
PG  - 2096-2111
LID - 10.1038/s41388-021-01690-z [doi]
AB  - 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 gamma-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.
FAU - Feng, Maoxiao
AU  - Feng M
AD  - Key Laboratory for Experimental Teratology of the Ministry of Education, 
      Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of 
      Medicine, Shandong University, Jinan, Shandong, China.
FAU - Wang, Yunshan
AU  - Wang Y
AUID- ORCID: 0000-0003-4873-054X
AD  - Department of Clinical Laboratory, The Second Hospital, Cheeloo College of 
      Medicine, Jinan, Shandong, China.
AD  - Biological Systems and Engineering Division, Lawrence Berkeley National 
      Laboratory, Berkeley, CA, USA.
FAU - Bi, Lei
AU  - Bi L
AUID- ORCID: 0000-0002-2951-0966
AD  - Biological Systems and Engineering Division, Lawrence Berkeley National 
      Laboratory, Berkeley, CA, USA.
AD  - School of Preclinical Medicine, Nanjing University of Chinese Medicine, Nanjing, 
      Jiangsu, China.
FAU - Zhang, Pengju
AU  - Zhang P
AD  - Biological Systems and Engineering Division, Lawrence Berkeley National 
      Laboratory, Berkeley, CA, USA.
AD  - Key Laboratory Experimental Teratology of the Ministry of Education, Department 
      of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Shandong 
      University, Jinan, Shandong, China.
FAU - Wang, Huaizhi
AU  - Wang H
AD  - Institute of Hepatopancreatobiliary Surgery, Chongqing General Hospital, 
      University of Chinese Academy of Sciences, Chongqing, China.
FAU - Zhao, Zhongxi
AU  - Zhao Z
AD  - School of Pharmaceutical Sciences, Shandong University, Jinan, Shandong, China.
FAU - Mao, Jian-Hua
AU  - Mao JH
AUID- ORCID: 0000-0001-9320-6021
AD  - Biological Systems and Engineering Division, Lawrence Berkeley National 
      Laboratory, Berkeley, CA, USA. jhmao@lbl.gov.
FAU - Wei, Guangwei
AU  - Wei G
AUID- ORCID: 0000-0001-5676-5326
AD  - Key Laboratory for Experimental Teratology of the Ministry of Education, 
      Department of Cell Biology, School of Basic Medical Sciences, Cheeloo College of 
      Medicine, Shandong University, Jinan, Shandong, China. gwwei@email.sdu.edu.cn.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20210224
PL  - England
TA  - Oncogene
JT  - Oncogene
JID - 8711562
RN  - 0 (CUL4A protein, human)
RN  - 0 (Cullin Proteins)
RN  - 0 (DTL protein, human)
RN  - 0 (Nuclear Proteins)
RN  - EC 2.7.11.1 (DNA-Activated Protein Kinase)
RN  - EC 2.7.11.1 (PRKDC protein, human)
SB  - IM
MH  - Carcinogenesis/*genetics
MH  - Cell Line, Tumor
MH  - Cell Nucleus/genetics
MH  - Cell Proliferation/genetics
MH  - Cullin Proteins/*genetics
MH  - DNA Damage/genetics
MH  - DNA End-Joining Repair/genetics
MH  - DNA Repair/genetics
MH  - DNA-Activated Protein Kinase/genetics
MH  - Genomic Instability/*genetics
MH  - Humans
MH  - Nuclear Proteins/*genetics
MH  - Precancerous Conditions/*genetics/pathology
PMC - PMC7979543
COIS- The authors declare no competing interests.
EDAT- 2021/02/26 06:00
MHDA- 2021/10/15 06:00
PMCR- 2021/02/24
CRDT- 2021/02/25 05:40
PHST- 2020/05/21 00:00 [received]
PHST- 2021/01/29 00:00 [accepted]
PHST- 2021/01/24 00:00 [revised]
PHST- 2021/02/26 06:00 [pubmed]
PHST- 2021/10/15 06:00 [medline]
PHST- 2021/02/25 05:40 [entrez]
PHST- 2021/02/24 00:00 [pmc-release]
AID - 10.1038/s41388-021-01690-z [pii]
AID - 1690 [pii]
AID - 10.1038/s41388-021-01690-z [doi]
PST - ppublish
SO  - Oncogene. 2021 Mar;40(11):2096-2111. doi: 10.1038/s41388-021-01690-z. Epub 2021 
      Feb 24.