Nucleotide excision repair and poly(ADP-ribose) polymerase 1 cooperate in HBV cccDNA synthesis: A potential viral therapeutic target

BACKGROUND r 0.31-0.43). CONCLUSIONS: ERCC1-XPF and TDP1-PARP1 complexes work in tandem to achieve cccDNA synthesis, indicating PARP1 inhibition as a promising therapeutic strategy for clearing cccDNA. IMPACT AND IMPLICATIONS: Blocking HBV cccDNA synthesis is imperative for reaching the goal of a cure for HBV. This study delineated the involvement of host NER endonucleases in resolving the flap structure on rcDNA and seeking an antiviral strategy by blocking the production of viral replication reservoirs. The NER ERCC1-XPF endonuclease and the topoisomerase 1-associated TDP1-PARP1 complex directly bind to the HBV genome in the human liver, where these factors correlate with the cccDNA levels. The ERCC1-XPF and TDP1-PARP1 complexes function in tandem to cleave the HBV rcDNA flap so that cccDNA synthesis can proceed. Thus, PARP1 inhibition could be a promising therapeutic strategy for cccDNA clearance.