DDB2 induces nuclear accumulation of the hepatitis B virus X protein independently of binding to DDB1

The hepatitis B virus (HBV) X protein (HBx) is critical for the life cycle of the virus. HBx associates with several host cell proteins including the DDB1 subunit of the damaged-DNA binding protein DDB. Recent studies on the X protein encoded by the woodchuck hepadnavirus have provided correlative e vidence indicating that the interaction with DDB1 is important for establis hment of infection by the virus. In addition, the interaction with DDB1 has been implicated in the nuclear localization of HBx. Because the DDB2 subun it of DDB is required for the nuclear accumulation of DDB1, we investigated the role of DDB2 in the nuclear accumulation of HBx. Here we show that exp ression of DDB2 increases the nuclear levels of HBx. Several C-terminal del etion mutants of DDB2 that fail to bind DDB1 are able to associate with HBx , suggesting that DDB2 may associate with HBx independently of binding to D DB1. We also show that DDB2 enhances the nuclear accumulation of HBx indepe ndently of binding to DDB1, since a mutant that does not bind DDB1 is able to enhance the nuclear accumulation of HBx. HBV infection is associated wit h liver pathogenesis. We show that the nuclear levels of DDB1 and DDB2 are tightly regulated in hepatocytes. Studies with regenerating mouse liver ind icate that during late G(1) phase the nuclear levels of both subunits of DD B are transiently increased, followed by a sharp decrease in S phase. Taken together, these results suggest that DDB1 and DDB2 would participate in th e nuclear functions of HBx effectively only during the late-G(1) phase of t he cell cycle.