HEPATITIS-B VIRUS-X PROTEIN INTERFERES WITH CELLULAR DNA-REPAIR

The hepatitis B virus X protein (HBx) is a broadly acting transactivat or implicated in the development of liver cancer. Recently, HBx has be en reported to interact with several different cellular proteins, incl uding our report of its binding to XAP-1, the human homolog of the sim ian repair protein UVDDB. In the present study, several HBx mutants we re used to localize the minimal domain of HBx required for binding to XAP-1/UVDDB to amino acids 55 to 101. The normal function of XAP-1/UVD DB is thought to involve binding to damaged DNA, the first step in nuc leotide excision repair (NER); therefore, we hypothesized that this in teraction may affect the cell's capacity to correct lesions in the gen ome. When tested in two independent assays that measure NER (unschedul ed DNA synthesis and host cell reactivation), the expression of HBx si gnificantly inhibited the ability of cells to repair damaged DNA. Unde r the assay conditions, HBx was expressed at a level similar to that p reviously observed during natural viral infection and was able to tran sactivate several target reporter genes. These results are consistent, vith a model in which HBx acts as a cofactor in hepatocarcinogenesis b y preventing the cell from efficiently repairing damaged DNA, thus lea ding to an accumulation of DNA mutations and, eventually, cancer. An a dverse effect on cellular DNA repair processes suggests a new mechanis m by which a tumor-associated virus might contribute to carcinogenesis .