title: Phosphorylation of Merkel cell polyomavirus large tumor antigen at serine 816 by ATM kinase induces apoptosis in host cells.
abstract: Merkel cell carcinoma is a highly aggressive form of skin cancer. Merkel cell polyomavirus (MCV) infection and DNA integration into the host genome correlate with 80% of all Merkel cell carcinoma cases. Integration of the MCV genome frequently results in mutations in the large tumor antigen (LT), leading to expression of a truncated LT that retains pRB binding but with a deletion of the C-terminal domain. Studies from our laboratory and others have shown that the MCV LT C-terminal helicase domain contains growth-inhibiting properties. Additionally, we have shown that host DNA damage response factors are recruited to viral replication centers. In this study, we identified a novel MCV LT phosphorylation site at Ser-816 in the C-terminal domain. We demonstrate that activation of the ATM pathway stimulated MCV LT phosphorylation at Ser-816, whereas inhibition of ATM kinase activity prevented LT phosphorylation at this site. In vitro phosphorylation experiments confirmed that ATM kinase is responsible for phosphorylating MCV LT at Ser-816. Finally, we show that ATM kinase-mediated MCV LT Ser-816 phosphorylation may contribute to the anti-tumorigenic properties of the MCV LT C-terminal domain.
authors.affiliation: From the The Wistar Institute, Philadelphia, Pennsylvania 19104.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: the Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, and.
authors.forename: Jason
authors.initials: J
authors.lastname: Diaz
authors.affiliation: the Department of Molecular Genetics, Lerner Research Institute, Cleveland, Ohio 44295.
authors.forename: Xin
authors.initials: X
authors.lastname: Wang
authors.affiliation: the Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, and.
authors.forename: Sabrina H
authors.initials: SH
authors.lastname: Tsang
authors.affiliation: the Department of Microbiology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania 19104, and jianyou@mail.med.upenn.edu.
authors.forename: Jianxin
authors.initials: J
authors.lastname: You
mesh_terms: D017304:Annexin A5 / Q000737:chemistry; D000952:Antigens, Polyomavirus Transforming / Q000378:metabolism*; D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins / Q000378:metabolism*; D045744:Cell Line, Tumor; D005982:Glutathione Transferase / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D059965:Merkel cell polyomavirus / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D017434:Protein Structure, Tertiary
chemical_list: D017304:Annexin A5; D000952:Antigens, Polyomavirus Transforming; D005982:Glutathione Transferase; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins
keywords: Apoptosis; Ataxia-Telangiectasia Mutated (ATM) Kinase; DNA Damage Response; Host-Pathogen Interaction; Merkel Cell Polyomavirus; Protein Phosphorylation; Tumor Virus