Human JC virus small tumour antigen inhibits nucleotide excision repair and sensitises cells to DNA-damaging agents.
The human JC virus (JCV) is potentially carcinogenic to humans as a Group 2B carcinogen, and it is ubiquitous in human populations. To investigate whether the small tumour (ST) antigen of the JCV contributes to genomic instability, we established cell lines stably expressing the JCV ST and examined its role in DNA repair. Results from host cell reactivation (HCR) assay revealed that the established cell lines exhibited lower nucleotide excision repair (NER) activity than the vector control cells did. The presence of γ-H2AX, a marker of DNA damage, indicated that the established cell line contained more DNA damage foci compared with vector control cells. Furthermore, the results of clonogenic analyses indicated that the JCV ST-expressing cells were more sensitive than the vector control cells to ultraviolet (UV) irradiation and cisplatin treatment. Micronuclei formation assay revealed that the JCV ST-positive cells presented more chromosomal breakages than did the JCV ST-negative cells, particularly after exposure to DNA-damaging agents. The xeroderma pigmentosum Group D protein, a DNA helicase involved in NER, was downregulated in the JCV ST-positive cells in response to UV irradiation. The effect of the protein phosphatase 2A (PP2A) inhibitor okadaic acid on NER was similar to that of the ST, which is a PP2A-binding protein. Therefore, the deactivation of the PP2A might underlie ST-mediated NER inhibition. The results of this study indicate that exposing JCV ST-positive cells to DNA-damaging agents causes genomic instability, which contributes to carcinogenesis. Our data provide further evidence on the association between the JCV ST and human cancer.
Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, School of Medicine, Chung Shan Medical University, Taichung, Taiwan jaulingh@mail.cjcu.edu.tw.
Jau-Ling
JL
Huang
Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan.
Chang-Shen
CS
Lin
Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Chia-Chu
CC
Chang
Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Yu-Ning
YN
Lu
Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Yu-Ling
YL
Hsu
Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Tzyy-Yue
TY
Wong
Department of Bioscience Technology, College of Health Science, Chang Jung Christian University, Tainan, Taiwan, Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung, Taiwan, Department of Biological Sciences, National Sun Yat-sen University, Kaohsiung, Taiwan, Division of Nephrology, Department of Internal Medicine, Changhua Christian Hospital, Changhua, Taiwan, School of Medicine, Chung Shan Medical University, Taichung, Taiwan.
Yu-Fei
YF
Wang
D000957:Antigens, Viral, Tumor / Q000494:pharmacology*; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects; D004249:DNA Damage / Q000187:drug effects*; D004260:DNA Repair / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D042822:Genomic Instability; D006801:Humans; D007577:JC Virus / Q000502:physiology*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000473:pathology*; D015162:Micronucleus Tests; D019319:Okadaic Acid / Q000494:pharmacology; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured
D000957:Antigens, Viral, Tumor; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D012333:RNA, Messenger; D019319:Okadaic Acid; D054648:Protein Phosphatase 2