Phosphorylation of Merkel Cell Polyomavirus Large T Antigen at Serine 816 by ATM Kinase Induces Apoptosis in Host Cells [Cell Biology]

December 5th, 2014 by Li, J., Diaz, J., Wang, X., Tsang, S. H., You, J.

Merkel cell carcinoma (MCC) 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 MCC. Integration of the MCV genome frequently results in mutations in the large T antigen (LT), which leads to expression of a truncated LT that retains retinoblastoma protein (pRb) binding but deletes the C-terminal domain. Studies from our lab and others have shown that the MCV LT C-terminal helicase domain contains growth inhibitory properties. Additionally, we have shown that host DNA Damage Response (DDR) factors are recruited to viral replication centers. In our current study, we identify a novel MCV LT phosphorylation site at serine 816 (S816) of the C-terminal domain. We demonstrate that activation of the ATM pathway stimulates MCV LT phosphorylation at S816, whereas inhibition of ATM kinase activity prevents LT phosphorylation at this site. In vitro phosphorylation experiments confirm that ATM kinase is responsible for phosphorylating MCV LT at S816. Finally, we show that ATM kinase-mediated MCV LT S816 phosphorylation may contribute to the MCV LT C-terminal domain′s anti-tumorigenic properties.