Identification of PARP1 as a Transcriptional Regulator of HBV Replication

Abstract

Chronic carriers of HBV have increased risk of developing liver diseases. To identify potential therapeutic targets for the treatment of chronic hepatitis B, host factors critical for transcription at the HBV core promoter were re-examined. This led to the discovery of PARP1, a nuclear enzyme involved in multiple cellular processing including DNA repair and transcription, as a novel factor that regulates HBV replication. Using the PARP1 binding site within the HBV core promoter as a model, the PARP1 recognition sequence which remained elusive till now is defined as ¿RNNWCAAA¿. Interestingly, binding of the octamer PARP1 motif resulted in the inhibition of PARP1 enzymatic activity. Consequently, the impairment of PARP1 activity in the cellular context was reduced DNA repair and enhanced cytotoxicity of cells treated with DNA damaging agents. It is proposed that the PARP1 binding motif alone can be used as a novel class of PARP1 inhibitors for the treatment of PARP1 dependent diseases including cancer, inflammation and viral infection.