Hepatitis B virus DNA polymerase explained

Hepatitis B virus DNA polymerase is a hepatitis B viral protein.^{[1] [2]} It is a DNA polymerase that can use either DNA or RNA templates and a ribonuclease H that cuts RNA in the duplex. Both functions are supplied by the reverse transcriptase (RT) domain.

Structure

The hepadnaviral P protein is organized into three domains: an N-terminal domain covering the terminal and the spacer, an RT domain related to every other reverse transcriptase domain, and a C-terminal domain regulating the RNase H activity.

Furthermore, hepadnavirus polymerases contain a terminal protein (TP) domain that contains a tyrosine residue that serves as a primer for the synthesis of the (-) DNA strand.

Function

The Hepatitis B virus (HBV) polymerase is a multifunctional enzyme, with both RNA-dependent and DNA-dependent polymerase functions, as well as an RNase H function. It acts on the HBV pre-genomic RNA (pgRNA) to reverse transcribe it to form a new rcDNA molecule within a new capsid. (The pgRNA has another function of being translated into the viral polymerase and core proteins).^[3]

HBV core protein dimers are required for packaging of the pgRNA/polymerase complex. Then, after viral polymerase binds to the packaging signal (Hɛ) found at the 5′ end of the pgRNA, they are incorporated into the viral capsid.^[4]

Inside the capsid, the pgRNA undergoes reverse transcription, which is initiated by protein priming at the tyrosine residue of the HBV polymerase. Thus, the (-) DNA strand is made. At the same time, the RNA template is degraded by the RNase H activity of the polymerase. A short RNA of about 15–18 nucleotides at the 5′ end of the pgRNA (including the 5′ DR1 sequence) is not degraded and it is used as primer for (+) DNA strand synthesis.

The resulting RC-DNA is partially double stranded. The (-) DNA strand is longer than a genome length, with a covalently bound polymerase and a redundant flap at the 5′ end. However, the (+) DNA strand synthesis is uncompleted by the polymerase, and there is a gap exists down to the 3′ end of the (+) DNA strand.

Notes and References

1. Ono-Nita SK, Kato N, Shiratori Y, Masaki T, Lan KH, Carrilho FJ, Omata M . YMDD motif in hepatitis B virus DNA polymerase influences on replication and lamivudine resistance: A study by in vitro full-length viral DNA transfection . Hepatology . 29 . 3 . 939–45 . March 1999 . 10051501 . 10.1002/hep.510290340 . free .
2. Shaw T, Mok SS, Locarnini SA . Inhibition of hepatitis B virus DNA polymerase by enantiomers of penciclovir triphosphate and metabolic basis for selective inhibition of HBV replication by penciclovir . Hepatology . 24 . 5 . 996–1002 . November 1996 . 8903366 . 10.1002/hep.510240504 . free .
3. Menéndez-Arias L, Álvarez M, Pacheco B . Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase: mechanism of action and resistance . Current Opinion in Virology . 8 . 1–9 . October 2014 . 24814823 . 10.1016/j.coviro.2014.04.005 .
4. Yang HC, Kao JH . Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance . Emerging Microbes & Infections . 3 . 9 . e64 . September 2014 . 26038757 . 4185362 . 10.1038/emi.2014.64 .