Novel poly (ADP‐ribose) polymerase 1 binding motif in hepatitis B virus core promoter impairs DNA damage repair

• Published in: Hepatology (Baltimore, Md.) Vol. 54; no. 4; pp. 1190 - 1198
• Main Authors: Ko, Hui‐Ling, Ren, Ee‐Chee
• Format: Journal Article
• Language: English
• Published: Hoboken Wiley Subscription Services, Inc., A Wiley Company 01.10.2011; Wiley; Wiley Subscription Services, Inc
• Subjects: Binding Sites; Biological and medical sciences; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - virology; Deoxyribonucleic acid; DNA; DNA Damage; DNA repair; DNA Repair - genetics; DNA Repair - physiology; Fluorescent Antibody Technique; Gastroenterology. Liver. Pancreas. Abdomen; Hep G2 Cells; Hepatitis; Hepatitis B; Hepatitis B - genetics; Hepatitis B virus; Hepatitis B virus - genetics; Hepatology; Humans; Immunoblotting; Liver Neoplasms - genetics; Liver Neoplasms - virology; Liver. Biliary tract. Portal circulation. Exocrine pancreas; Medical sciences; Poly (ADP-Ribose) Polymerase-1; Poly(ADP-ribose) Polymerases - genetics; Poly(ADP-ribose) Polymerases - metabolism; Promoter Regions, Genetic - genetics; Promoter Regions, Genetic - physiology; Sensitivity and Specificity; Viral Load; Virus; Promoter; Hepadnaviridae; DNA; Gastroenterology; Orthohepadnavirus; Hepatitis B virus; ADP
• ISSN: 0270-9139; 1527-3350
• DOI: 10.1002/hep.24502

It is well‐established that hepatitis B virus (HBV) infection is associated with the development of hepatocellular carcinoma (HCC), but patients with high viral DNA load have significantly higher risk. As host factors are required for efficient viral replication and may, therefore, contribute to high viral DNA load, we screened for host factors that can transcriptionally activate the HBV core promoter (HBVCP). We report here that poly (ADP‐ribose) polymerase 1 (PARP1), which is known for its DNA repair activity, binds prominently to an octamer motif in the HBVCP and increases transcriptional efficiency. By utilizing a series of single base substitutions at each nucleotide position of the octamer, the PARP1 binding motif can be defined as “RNNWCAAA.” Intriguingly, introduction of a vector construct bearing tandem repeats of the octamer motif was able to impair the DNA repair function of PARP1. This finding suggests that HBV viral DNA contains specific sequence motifs that may play a role in disrupting the DNA repair pathways of infected hepatocytes. Conclusion: This study has identified a novel octamer motif in the HBVCP that binds PARP1, and this interaction increases the replication efficiency of HBV. The presence of this octamer motif in hepatocytes was shown to inhibit the DNA repair capacity of PARP1, potentially contributing to the development of HCC. (HEPATOLOGY 2011;)