Inhibition of DNA repair by the hepatitis B virus large surface antigen pre-S2 mutant

1861 Chronic HBV infection is a major global cause of hepatocellular carcinoma (HCC). HBV encodes three types of surface proteins that are different in sizes. Two major types of deletion mutants in HBS gene have been identified, and designated pre-S 1 and pre-S 2 mutant large HBsAg (LHBS). The pre-S mutant LHBS accumulate in hepatocytes and reveal ground-glass hepatocytes (GGH), which are often seen in patients with chronic HBV infection. Hepatocytes expressing the pre-S 2 mutant LHBS cluster into groups and exhibit clonal expansion and growth advantage. We previously reported that the pre-S 2 mutant LHBS induces ER stress-dependent oxidative stress and oxidative DNA damage in vitro and in vivo . We also found that the pre-S 2 mutant LHBS is associated with the Jun-activation domain binding protein 1 (JAB1), a subunit of the COP9 signalosome complex, leading to cyclin-dependent kinase inhibitor p27 Kip1 degradation, Cdk2 activation, retinoblastoma (RB) hyperphosphorylation and cell cycle progression. By yeast two-hybrid screening assays, we have also found that the pre-S 2 mutant but not the wild-type LHBS interacts with importin α1, an essential subunit in NPC (nuclear pore complex). Importin α1 has been found to interact with DNA repair protein NBS1 and blocks its nuclear translocation, resulting in defect of DNA repair. We found that the pre-S 2 mutant LHBS induces cytosolic retention of NBS1 protein and defects in homologous recombination. We believe that this is one of the major mechanisms that lead to pre-S 2 mutant LHBS-related genomic instabilities. The functional domains involved in the interaction between the pre-S 2 LHBS and importin α1 are under search. The results of these studies will help us elucidate the structural differences in the pre-S 2 mutant from the wild-type LHBS and develop potential prophylactic/therapeutic drugs for HCC caused by pre-S 2 mutant LHBS.