Phosphorylation of Merkel Cell Polyomavirus Large Tumor Antigen at Serine 816 by ATM Kinase Induces Apoptosis in Host Cells

This is the authors' abstract. We don't add key points for this paper.

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.Phosphorylation regulates Merkel cell polyomavirus (MCV) large tumor antigen (LT) activity. Results MCV LT is phosphorylated by ATM kinase at Ser-816. Conclusion Ser-816 phosphorylation by ATM allows MCV LT to arrest cell growth and induce apoptosis. Significance Ser-816 phosphorylation-induced apoptosis may explain why the C-terminal domain of LT is negatively selected in MCV-related tumors.