title: Defective DNA repair and cell cycle arrest in cells expressing Merkel cell polyomavirus T antigen.
abstract: 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.
authors.affiliation: Department of Dermatology, University of California, San Francisco, CA, USA.
authors.forename: Stephanie K
authors.initials: SK
authors.lastname: Demetriou
authors.forename: Katherine
authors.initials: K
authors.lastname: Ona-Vu
authors.forename: Erin M
authors.initials: EM
authors.lastname: Sullivan
authors.forename: Tiffany K
authors.initials: TK
authors.lastname: Dong
authors.forename: Shu-Wei
authors.initials: SW
authors.lastname: Hsu
authors.forename: Dennis H
authors.initials: DH
authors.lastname: Oh
mesh_terms: D000952:Antigens, Polyomavirus Transforming / Q000276:immunology / Q000378:metabolism*; D000957:Antigens, Viral, Tumor / Q000276:immunology / Q000378:metabolism*; D015266:Carcinoma, Merkel Cell / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D059447:Cell Cycle Checkpoints; D002470:Cell Survival; D004249:DNA Damage; D004260:DNA Repair; D005347:Fibroblasts / Q000166:cytology / Q000378:metabolism / Q000528:radiation effects; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D059965:Merkel cell polyomavirus / Q000276:immunology* / Q000378:metabolism; D027601:Polyomavirus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D012333:RNA, Messenger / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism / Q000821:virology; D014407:Tumor Cells, Cultured; D014412:Tumor Virus Infections / Q000276:immunology* / Q000378:metabolism / Q000821:virology; D014466:Ultraviolet Rays
chemical_list: D000952:Antigens, Polyomavirus Transforming; D000957:Antigens, Viral, Tumor; D012333:RNA, Messenger