A major mechanism of cellular resistance to viral invasion involves genes from the interferon signaling pathway, called ISGs (interferon stimulated genes). Global transcriptional profiling studies have linked increased expression of ISG95 (KIAA0082) to response to interferon treatment and viral infection, suggesting that it may be part of the cellular defense against viral replication. In this work, we show that the ISG95 promoter can drive interferon-induced transcription of a reporter gene in Vero cells. Recombinant ISG95 shows RNA- and S-adenosyl-methionine binding and protein m ethyl transferase activity in vitro. ISG95 interacts with the C-terminal domain of RNA polymerase II, which is consistent with its nuclear localization and with the predicted function of the WW domain found in the C-terminal region of ISG95. The results presented in this work indicate that ISG95 is part of the interferon response pathway and functions in the pre-mRNA processing events mediated by the C-terminal domain of the RNA polymerase II. (c) 2008 Elsevier Inc. All rights reserved.