Fig. 7: A putative model of the repair of HBV rcDNA.
From: Hepatitis B virus cccDNA is formed through distinct repair processes of each strand
The HBV polymerase adduct is first removed by redundant factors FEN-1 (step i) and TDP2 (step i’). The subsequent repair of the minus- and plus-strands are independent of each other, and the repair of the minus-strand only requires FEN-1 and LIG1 and proceeding, as steps -i and -ii. The repair of the plus-strand resembles Okazaki fragment synthesis, requiring more steps as shown from steps +ii to +vi. First, the RFC complex recognizes the 3′ end of the plus strand and loads PCNA to this primer-template junction (step +ii). PCNA then recruits POLδ via the PCNA-interacting peptide (PIP) sequence on POLδ (step +iii). This step can be specifically inhibited by the p21WAF1 peptide (KRRQTSMTDFYHSKRRLIFS). Subsequently, POLδ is activated by PCNA and fills the ssDNA gap and displaces the RNA primer on the 5′-end of the plus-strand (step +iv). This step can be delayed by aphidicolin treatment. The displaced RNA primer adopts a flap structure that can be recognized and removed by FEN-1, leaving one nick on the plus-strand (step +v). At last, LIG1 ligates this nick and completes the repair of the plus-strand (step +vi).
