Merkel cell polyomavirus (MCPyV) is the causative agent of an aggressive skin tumor, Merkel cell carcinoma (MCC). The viral genome is integrated into the tumor genome and harbors nonsense mutations in the helicase domain of large T antigen (LTAg). However, the molecular mechanisms by which the viral genome gains the tumor-specific mutations remain to be elucidated. Focusing on host cytosine deaminases APOBEC3s (A3s), we find that A3A, A3B, or A3G introduces A3-specific mutations into episomal MCPyV genomes in MCPyV-replicating 293-derivative cells. Sequence analysis of MCPyV genomes retrieved from the NCBI database revealed a decrease of TpC dinucleotide, a preferred target for A3A and A3B, in the 3'-region of the LTAg-coding sequence. The viral DNA isolated from tumors contained mutated cytosines, with a remarkable bias toward TpC dinucleotide. Analysis of publicly available microarray data showed that expression of interferon-γ and cytotoxic T cell markers was positively correlated with A3A, A3B, and A3G levels in MCPyV-positive but not in MCPyV-negative tumors. Finally, interferon-γ treatment induced A3B and A3G expression in the MCPyV-positive MCC cell line, MS-1. These results suggest that the interferon-γ-A3B axis plays pivotal roles in evolutionally shaping MCPyV genomic sequences and in generating tumor-specific LTAg mutations during MCC carcinogenesis.
Categories: Idiopathic Pulmonary Fibrosis
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