Hepatitis B virus DNA polymerase

Last updated
Protein P (DNA polymerase / RNase H)
HBV Genome.svg
The genome organisation of HBV; the genes overlap. ORF P, in blue, encodes Hepatitis B virus DNA polymerase.
Identifiers
Organism Hepatitis B virus ayw/France/Tiollais/1979
SymbolP
UniProt P03156
Protein P
Identifiers
Symbol?
InterPro IPR037531

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.

Contents

Structure

The hepadnaviral P protein is organized into three domains: an N-terminal domain (InterPro :  IPR000201 ) covering the terminal and the spacer, an RT domain related to every other RT domain, and a C-terminal domain (InterPro :  IPR001462 ) regulating the RNase H activity.

Function

In HBV the pgRNA, is translated into the viral polymerase and core proteins, and then encapsidated and reverse transcribed to form a new rcDNA molecule. In this stage, the HBV polymerase has some tasks and functions. The HBV polymerase is a multifunctional enzyme with RNA-dependent and DNA-dependent polymerase and RNase H activities. [3] 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. [3]

In reverse transcription steps, existing of HBV core protein dimers is 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. [3] [4] Inside the capsid, the pgRNA undergoes reverse transcription, which is initiated by protein priming at the tyrosine residue of the HBV polymerase. Thus, (-) DNA strand is made. [4] At the same time, degradation of the RNA template is took place 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. [3]

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. [4]

Related Research Articles

Complementary DNA Single-stranded DNA synthesized from an RNA template by the action of an RNA-dependent DNA polymerase

In genetics, complementary DNA (cDNA) is DNA synthesized from a single-stranded RNA template in a reaction catalyzed by the enzyme reverse transcriptase. cDNA is often used to clone eukaryotic genes in prokaryotes. When scientists want to express a specific protein in a cell that does not normally express that protein, they will transfer the cDNA that codes for the protein to the recipient cell. In molecular biology, cDNA is also generated to analyze transcriptomic profiles in bulk tissue, single cells, or single nuclei in assays such as microarrays and RNA-seq.

Retrovirus Family of viruses

A retrovirus is a type of virus that inserts a copy of its RNA genome into the DNA of a host cell that it invades, thus changing the genome of that cell. Once inside the host cell's cytoplasm, the virus uses its own reverse transcriptase enzyme to produce DNA from its RNA genome, the reverse of the usual pattern, thus retro (backwards). The new DNA is then incorporated into the host cell genome by an integrase enzyme, at which point the retroviral DNA is referred to as a provirus. The host cell then treats the viral DNA as part of its own genome, transcribing and translating the viral genes along with the cell's own genes, producing the proteins required to assemble new copies of the virus.

Reverse transcriptase

A reverse transcriptase (RT) is an enzyme used to generate complementary DNA (cDNA) from an RNA template, a process termed reverse transcription. Reverse transcriptases are used by certain viruses such as HIV and the hepatitis B virus to replicate their genomes, by retrotransposon mobile genetic elements to proliferate within the host genome, and by eukaryotic cells to extend the telomeres at the ends of their linear chromosomes. Contrary to a widely held belief, the process does not violate the flows of genetic information as described by the classical central dogma, as transfers of information from RNA to DNA are explicitly held possible.

Hepatitis D is a type of viral hepatitis caused by the hepatitis delta virus (HDV), a small spherical enveloped particle that shares similarities with both a viroid and virusoid. HDV is one of five known hepatitis viruses: A, B, C, D, and E. HDV is considered to be a satellite because it can propagate only in the presence of the hepatitis B virus (HBV). Transmission of HDV can occur either via simultaneous infection with HBV (coinfection) or superimposed on chronic hepatitis B or hepatitis B carrier state (superinfection).

<i>Hepadnaviridae</i>

Hepadnaviridae is a family of viruses. Humans, apes, and birds serve as natural hosts. There are currently 18 species in this family, divided among 5 genera. Its best-known member is hepatitis B virus. Diseases associated with this family include: liver infections, such as hepatitis, hepatocellular carcinomas, and cirrhosis. It is the sole family in the order Blubervirales.

Picornavirus

Picornaviruses are a group of related nonenveloped RNA viruses which infect vertebrates including mammals and birds. They are viruses that represent a large family of small, positive-sense, single-stranded RNA viruses with a 30-nm icosahedral capsid. The viruses in this family can cause a range of diseases including the common cold, poliomyelitis, meningitis, hepatitis, and paralysis.

Ribonuclease H

Ribonuclease H is a family of non-sequence-specific endonuclease enzymes that catalyze the cleavage of RNA in an RNA/DNA substrate via a hydrolytic mechanism. Members of the RNase H family can be found in nearly all organisms, from bacteria to archaea to eukaryotes.

Cauliflower mosaic virus (CaMV) is a member of the genus Caulimovirus, one of the six genera in the family Caulimoviridae, which are pararetroviruses that infect plants. Pararetroviruses replicate through reverse transcription just like retroviruses, but the viral particles contain DNA instead of RNA.

Baltimore classification Virus classification system made by David Baltimore

Baltimore classification is a system used to classify viruses based on their manner of messenger RNA (mRNA) synthesis. By organizing viruses based on their manner of mRNA production, it is possible to study viruses that behave similarly as a distinct group. Seven Baltimore groups are described that take into consideration whether the viral genome is made of deoxyribonucleic acid (DNA) or ribonucleic acid (RNA), whether the genome is single- or double-stranded, and whether the sense of a single-stranded RNA genome is positive or negative.

Multicopy single-stranded DNA

Multicopy single-stranded DNA (msDNA) is a type of extrachromosomal satellite DNA that consists of a single-stranded DNA molecule covalently linked via a 2'-5'phosphodiester bond to an internal guanosine of an RNA molecule. The resultant DNA/RNA chimera possesses two stem-loops joined by a branch similar to the branches found in RNA splicing intermediates. The coding region for msDNA, called a "retron", also encodes a type of reverse transcriptase, which is essential for msDNA synthesis.

RNA-dependent RNA polymerase

RNA-dependent RNA polymerase or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyses synthesis of the RNA strand complementary to a given RNA template. This is in contrast to typical DNA-dependent RNA polymerases, which all organisms use to catalyze the transcription of RNA from a DNA template.

Hepatitis B Human viral infection

Hepatitis B is an infectious disease caused by the hepatitis B virus (HBV) that affects the liver; it is a type of viral hepatitis. It can cause both acute and chronic infection. Many people have no symptoms during the initial infection. In acute infection, some may develop a rapid onset of sickness with vomiting, yellowish skin, tiredness, dark urine, and abdominal pain. Often these symptoms last a few weeks and rarely does the initial infection result in death. It may take 30 to 180 days for symptoms to begin. In those who get infected around the time of birth 90% develop chronic hepatitis B while less than 10% of those infected after the age of five do. Most of those with chronic disease have no symptoms; however, cirrhosis and liver cancer may eventually develop. Cirrhosis or liver cancer occur in about 25% of those with chronic disease.

HBx

HBx is a hepatitis B viral protein. It is 154 amino acids long and interferes with transcription, signal transduction, cell cycle progress, protein degradation, apoptosis and chromosomal stability in the host. It forms a heterodimeric complex with its cellular target protein, and this interaction dysregulates centrosome dynamics and mitotic spindle formation. It interacts with DDB1 redirecting the ubiquitin ligase activity of the CUL4-DDB1 E3 complexes, which are intimately involved in the intracellular regulation of DNA replication and repair, transcription and signal transduction.

<i>Hepatitis B virus</i> Species of the genus Orthohepadnavirus

Hepatitis B virus (HBV), is a partially double-stranded DNA virus, a species of the genus Orthohepadnavirus and a member of the Hepadnaviridae family of viruses. This virus causes the disease hepatitis B.

cccDNA is a special DNA structure that arises during the propagation of some viruses in the cell nucleus and may remain permanently there. It is a double-stranded DNA that originates in a linear form that is ligated by means of DNA ligase to a covalently closed ring. In most cases, transcription of viral DNA can occur from the circular form only. The cccDNA of viruses is also known as episomal DNA or occasionally as a minichromosome.

The transmission of hepadnaviruses between their natural hosts, humans, non-human primates, and birds, including intra-species host transmission and cross-species transmission, is a topic of study in virology.

Retroviral ribonuclease H

The retroviral ribonuclease H is a catalytic domain of the retroviral reverse transcriptase (RT) enzyme. The RT enzyme is used to generate complementary DNA (cDNA) from the retroviral RNA genome. This process is called reverse transcription. To complete this complex process, the retroviral RT enzymes need to adopt a multifunctional nature. They therefore possess 3 of the following biochemical activities: RNA-dependent DNA polymerase, ribonuclease H, and DNA-dependent DNA polymerase activities ). Like all RNase H enzymes, the retroviral RNase H domain cleaves DNA/RNA duplexes and will not degrade DNA or unhybridized RNA.

Riboviria is a realm of viruses that includes all viruses that use a homologous RNA-dependent polymerase for replication. It includes RNA viruses that encode an RNA-dependent RNA polymerase; and, it includes reverse-transcribing viruses that encode an RNA-dependent DNA polymerase. RNA-dependent RNA polymerase (RdRp), also called RNA replicase, produces RNA from RNA. RNA-dependent DNA polymerase (RdDp), also called reverse transcriptase (RT), produces DNA from RNA. These enzymes are essential for replicating the viral genome and transcribing viral genes into messenger RNA (mRNA) for translation of viral proteins.

<i>Ground squirrel hepatitis virus</i>

Ground squirrel hepatitis virus, abbreviated GSHV, is a partially double-stranded DNA virus that is closely related to human Hepatitis B virus (HBV) and Woodchuck hepatitis virus (WHV). It is a member of the family of viruses Hepadnaviridae and the genus Orthohepadnavirus. Like the other members of its family, GSHV has high degree of species and tissue specificity. It was discovered in Beechey ground squirrels, Spermophilus beecheyi, but also infects Arctic ground squirrels, Spermophilus parryi. Commonalities between GSHV and HBV include morphology, DNA polymerase activity in genome repair, cross-reacting viral antigens, and the resulting persistent infection with viral antigen in the blood (antigenemia). As a result, GSHV is used as an experimental model for HBV.

<i>Woolly monkey hepatitis B virus</i> Species of virus

The woolly monkey hepatitis B virus (WMHBV) is a viral species of the Orthohepadnavirus genus of the Hepadnaviridae family. Its natural host is the woolly monkey (Lagothrix), an inhabitant of South America categorized as a New World primate. WMHBV, like other hepatitis viruses, infects the hepatocytes, or liver cells, of its host organism. It can cause hepatitis, liver necrosis, cirrhosis, and hepatocellular carcinoma. Because nearly all species of Lagothrix are threatened or endangered, researching and developing a vaccine and/or treatment for WMHBV is important for the protection of the whole woolly monkey genus.

References

  1. Ono-Nita SK, Kato N, Shiratori Y, Masaki T, Lan KH, Carrilho FJ, Omata M (March 1999). "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. doi: 10.1002/hep.510290340 . PMID   10051501.
  2. Shaw T, Mok SS, Locarnini SA (November 1996). "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. doi: 10.1002/hep.510240504 . PMID   8903366.
  3. 1 2 3 4 Menéndez-Arias L, Álvarez M, Pacheco B (October 2014). "Nucleoside/nucleotide analog inhibitors of hepatitis B virus polymerase: mechanism of action and resistance". Current Opinion in Virology. 8: 1–9. doi:10.1016/j.coviro.2014.04.005. PMID   24814823.
  4. 1 2 3 Yang HC, Kao JH (September 2014). "Persistence of hepatitis B virus covalently closed circular DNA in hepatocytes: molecular mechanisms and clinical significance". Emerging Microbes & Infections. 3 (9): e64. doi:10.1038/emi.2014.64. PMC   4185362 . PMID   26038757.