Hepatitis B virus pre-S2 mutant LHBS induced DNA breakages and genomic instability.

ABSTRACT: Although hepatitis B virus (HBV) has been established to cause hepatocellular carcinoma (HCC), the exact mechanism remains to be clarified. Type II ground glass hepatocytes (GGH) harboring the HBV pre-S2 mutant large surface protein have been recognized as morphologically distinct hallmark of HCC in advanced stages of chronic HBV infection. Considering its pre-neoplastic nature, we hypothesized that type II GGH may exhibit high genomic instability, which is important for the carcinogenic process in chronic HBV carriers. In this study we found that pre-S2 mutant LHBS directly interacted with importin 1, the key factor that recognizes cargos undergoing nuclear transportation mediated by the importin 1 associated nuclear pore complex (NPC). By interacting with importin 1, which inhibits its function as an NPC factor, pre-S2 mutant LHBS blocked nuclear transportation of an essential DNA repair and recombination factor Nijmegen breakage syndrome 1 (NBS1) upon DNA damage, thereby delaying formation of nuclear foci at the sites of DNA double strand breaks. Pre-S2 mutant LHBS was also found to block NBS1-mediated homologous recombination repair and induce multi-nucleation of cells. In addition, pre-S2 mutant LHBS transgenic mice showed genomic instability indicated by increased global gene copy number variations (CNV), which were significantly higher than those in hepatitis B virus X mice, indicating that pre-S2 mutant LHBS is the major viral oncoprotein inducing genomic instability in HBV-infected hepatocytes. Consistently, the human type II GGHs in HCC patients exhibited increased DNA double-strand breaks representing significant genomic instability. In conclusion, type II GGH harboring HBV pre-S2 mutant oncoprotein represents a high-risk marker for the loss of genome integrity in chronic HBV carriers and explains the complex chromosome changes in HCCs. Non-tumorous liver sections from four each the HBx and pre-S2 mutant LHBS transgenic mice and 3 double transgenic mice between 9 and 22 months old were examined for gene gain and loss.

ORGANISM(S): Mus musculus

SUBMITTER: Wenya Huang 

PROVIDER: E-GEOD-61378 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress