Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen
| Autor: | Demetriou, Stephanie K, Ona-Vu, Katherine, Sullivan, Erin M, Dong, Tiffany K, Hsu, Shu-Wei, Oh, Dennis H |
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| Rok vydání: | 2012 |
| Předmět: |
ultraviolet radiation
Skin Neoplasms DNA Repair Ultraviolet Rays Cell Survival Messenger Immunoblotting Oncology and Carcinogenesis polyomavirus Merkel cell carcinoma Genetics Humans 2.1 Biological and endogenous factors Climate-Related Exposures and Conditions Viral Oncology & Carcinogenesis Antigens Aetiology Cancer Polyomavirus Infections Cultured Tumor Reverse Transcriptase Polymerase Chain Reaction Carcinoma Cell Cycle Checkpoints Fibroblasts Flow Cytometry Tumor Cells Tumor Virus Infections Merkel cell polyomavirus Merkel Cell Polyomavirus Transforming RNA cell cycle DNA Damage |
| Zdroj: | International journal of cancer, vol 131, iss 8 |
| Popis: | The pathways by which Merkel cell polyomavirus (MCV) infection contributes to the formation of Merkel cell carcinomas are important for understanding the pathogenesis of these cancers. We hypothesized that MCV T antigen suppresses normal responses to ultraviolet radiation (UVR)-induced DNA damage. An MCV-infected cell line (MKL-1) exhibited UVR hypersensitivity, impaired repair of DNA lesions and cell cycle arrest after UVR, as well as reduced levels of the DNA damage recognition protein, XPC. When ectopically expressed in uninfected UISO cells, mutant but not wild-type T antigen resulted in loss of repair of UVR-induced cyclobutane pyrimidine dimers and reductions in XPC, p53 and p21 levels, whereas both wild-type and mutant T antigen inhibited cell cycle arrest after UVR. Similarly, only mutant T antigen in normal fibroblasts inhibited DNA repair and XPC expression, while both mutant and wild-type T antigens produced cell cycle dysregulation. Wild-type T antigen expression produced large T, 57 kT and small T antigens while mutant T antigen was only detectable as a truncated large T antigen protein. Expression of wild-type large T antigen but not small T antigen inhibited the G1 checkpoint in UISO cells, but neither wild-type large T nor small T antigens affected DNA repair, suggesting that large T antigen generates cell cycle defects, and when mutated may also impair DNA repair. These results indicate that T antigen expression by MCV can inhibit key responses to UVR-induced DNA damage and suggest that progressive MCV-mediated abrogation of genomic stability may be involved in Merkel cell carcinogenesis. |
| Databáze: | OpenAIRE |
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