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Reduced ADP ‐ribosylation by PARP 1 natural polymorphism V762A and by PARP 1 inhibitors enhance Hepatitis B virus replication
Author(s) -
Ko H. L.,
Ng H. J.,
Goh E. H.,
Ren E. C.
Publication year - 2013
Publication title -
journal of viral hepatitis
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.329
H-Index - 100
eISSN - 1365-2893
pISSN - 1352-0504
DOI - 10.1111/jvh.12100
Subject(s) - poly adp ribose polymerase , hepatitis b virus , biology , viral replication , microbiology and biotechnology , transcription (linguistics) , virology , polymerase , gene , virus , genetics , linguistics , philosophy
Summary H ep G 2 and H uh7 cell lines are frequently used as models to study viral hepatitis and hepatocellular carcinoma. However, they exhibit significantly different capacities in their ability to support hepatitis B virus ( HBV ) replication. To investigate the basis for this, transcription factor–binding motifs at the HBV core promoter ( HBVCP ) were tested in luciferase reporter constructs to identify the possible role of host factors. Among the transcription factors screened: PARP 1, SP 1, HNF 4α, HNF 3, h B 1 F and HNF 1, deletion of the PARP 1 binding motif abrogated transcriptional activity at the HBVCP in H ep G 2 but not H uh7 cells. Sequencing of the PARP 1 gene revealed that H ep G 2 cells carried an A la762 allele which has low ADP ‐ribosylation activity, which was shown to have increased PARP 1 binding affinity to its cognate motif thus resulting in higher transcriptional activity. PARP 1 inhibitors that are being developed as broad cancer therapeutics also target PARP 1 ADP ‐ribosylation enzymatic function. Four PARP 1 inhibitors: P J‐34, ABT 888, AZD 2281 and AG 014699 were tested for their effect on HBV replication. All four small molecules effectively enhanced HBV replication in vitro , confirming the role of PARP 1 in HBV replication and that alteration of ADP ‐ribosylation by mutation or drugs can affect HBV replication. Our data demonstrate that natural polymorphisms in the host affecting proteins such as PARP 1 can have a significant effect on HBV replication. Hence, patients who are infected with HBV and are on clinical trials involving PARP 1 inhibitors may be at risk from unintended side‐effects such as exacerbation of HBV replication.