EBNA-1, THE MAJOR NUCLEAR ANTIGEN OF EPSTEIN-BARR-VIRUS, RESEMBLES RGG RNA-BINDING PROTEINS

Nuclear antigen 1 (EBNA-1) is one of the key functions of the oncogeni c DNA virus, Epstein-Barr virus (EBV), and is the only viral protein c onsistently expressed in EBV-associated malignancies. EBNA-1 binds in a site-specific manner to the viral DNA and is essential for viral rep lication, as well as for maintaining the genome as an extrachromosomal episome within infected cells. EBNA-1 is not recognized by the cellul ar immune system. Here we demonstrate that, in addition to its known D NA binding properties, EBNA-1 can also act as a strong RNA binding pro tein, interacting with diverse substrates in vitro, including the EBV- encoded RNA polymerase III transcript EBER1 and the HIV-encoded transa ctivation response (TAR) element. We also show that EBNA-1 can bind ex on sequences derived from its own RNA expressed from the Fp promoter, as found in Burkitt's lymphoma-related cells and in nasopharyngeal car cinomas. EBNA-1 has been identified as a component in an RNA complex; moreover, an anti-EBNA-1 antibody 1H4-1, that does not inhibit DNA bin ding, blocks binding to RNA. Arginine/glycine-containing (so-called 'R GG') motifs have been found in an increasing number of proteins that i nteract with RNA. The EBV antigen contains three potential 'RGG' motif s located around an internal glycine/alanine-rich repetitive sequence in the protein, and outside the region of EBNA-1 mapped previously as essential for viral DNA replication and other functionally defined pro perties. These motifs could be involved in the observed binding betwee n EBNA-1 and RNA. Our data suggest that the mechanism of RNA binding m ay be complex and raise the possibility that EBNA-1 may play a role in EBV-associated tumours through transcriptional (or posttranscriptiona l) viral and/or cellular regulation.