RNA-dependent RNA polymerase

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RNA-dependent RNA polymerase
HCV NS5B RdRP stalled 4WTG.png
Stalled HCV RNA replicase (NS5B), in complex with sofosbuvir (PDB 4WTG).
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EC no. 2.7.7.48
CAS no. 9026-28-2
Databases
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ExPASy NiceZyme view
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NCBI proteins

RNA-dependent RNA polymerase (RdRp) or RNA replicase is an enzyme that catalyzes the replication of RNA from an RNA template. Specifically, it catalyzes 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.

Contents

RdRp is an essential protein encoded in the genomes of most RNA-containing viruses that lack a DNA stage, [1] [2] including SARS-CoV-2. Some eukaryotes also contain RdRps, which are involved in RNA interference and differ structurally from viral RdRps.

History

Viral RdRps were discovered in the early 1960s from studies on mengovirus and polio virus when it was observed that these viruses were not sensitive to actinomycin D, a drug that inhibits cellular DNA-directed RNA synthesis. This lack of sensitivity suggested the action of a virus-specific enzyme that could copy RNA from an RNA template. [3]

Distribution

Viruses-07-02829-g001a.png
Viruses-07-02829-g001b.webp
Structure and replication elongation mechanism of a RdRp

RdRps are highly conserved in viruses and are related to telomerase, though the reason for this was an ongoing question as of 2009. [4] The similarity led to speculation that viral RdRps are ancestral to human telomerase. [5]

The most famous example of RdRp is in the polio virus. The viral genome is composed of RNA, which enters the cell through receptor-mediated endocytosis. From there, the RNA acts as a template for complementary RNA synthesis. The complementary strand acts as a template for the production of new viral genomes that are packaged and released from the cell ready to infect more host cells. The advantage of this method of replication is that no DNA stage complicates replication. The disadvantage is that no 'back-up' DNA copy is available. [6]

Many RdRps associate tightly with membranes making them difficult to study. The best-known RdRps are polioviral 3Dpol, vesicular stomatitis virus L, [7] and hepatitis C virus NS5B protein.

Many eukaryotes have RdRps that are involved in RNA interference: these amplify microRNAs and small temporal RNAs and produce double-stranded RNA using small interfering RNAs as primers. [8] These RdRps are used in the defense mechanisms and can be appropriated by RNA viruses. [9] Their evolutionary history predates the divergence of major eukaryotic groups. [10]

Replication

RdRp differs from DNA dependent RNA polymerase as it catalyzes RNA synthesis of strands complementary to a given RNA template. The RNA replication process is a four-step mechanism:

RNA synthesis can be performed by a primer-independent (de novo) or a primer-dependent mechanism that utilizes a viral protein genome-linked (VPg) primer. [13] The de novo initiation consists in the addition of a NTP to the 3'-OH of the first initiating NTP. [13] During the following elongation phase, this nucleotidyl transfer reaction is repeated with subsequent NTPs to generate the complementary RNA product. Termination of the nascent RNA chain produced by RdRp is not completely known, however, RdRp termination is sequence-independent. [14]

One major drawback of RNA-dependent RNA polymerase replication is the transcription error rate. [13] RdRps lack fidelity on the order of 104 nucleotides, which is thought to be a direct result of inadequate proofreading. [13] This variation rate is favored in viral genomes as it allows for the pathogen to overcome host defenses trying to avoid infection, allowing for evolutionary growth. [15]

Structure

Overview of the flavivirus RdRp structure based on West Nile Virus (WNV) NS5Pol 1-s2.0-S0166354209005385-gr10.jpg
Overview of the flavivirus RdRp structure based on West Nile Virus (WNV) NS5Pol

Viral/prokaryotic RdRp, along with many single-subunit DdRp, employ a fold whose organization has been linked to the shape of a right hand with three subdomains termed fingers, palm, and thumb. [16] Only the palm subdomain, composed of a four-stranded antiparallel beta sheet with two alpha helices, is well conserved. In RdRp, the palm subdomain comprises three well-conserved motifs (A, B, and C). Motif A (D-x(4,5)-D) and motif C (GDD) are spatially juxtaposed; the aspartic acid residues of these motifs are implied in the binding of Mg2+ and/or Mn2+. The asparagine residue of motif B is involved in selection of ribonucleoside triphosphates over dNTPs and, thus, determines whether RNA rather than DNA is synthesized. [17] The domain organization [18] and the 3D structure of the catalytic centre of a wide range of RdRps, even those with a low overall sequence homology, are conserved. The catalytic center is formed by several motifs containing conserved amino acid residues.[ citation needed ]

Eukaryotic RNA interference requires a cellular RdRp (c RdRp). Unlike the "hand" polymerases, they resemble simplified multi-subunit DdRPs, specifically in the catalytic β/β' subunits, in that they use two sets of double-psi β-barrels in the active site. QDE1 ( Q9Y7G6 ) in Neurospora crassa , which has both barrels in the same chain, [19] is an example of such a c RdRp enzyme. [20] Bacteriophage homologs of c RdRp, including the similarly single-chain DdRp yonO ( O31945 ), appear to be closer to c RdRps than DdRPs are. [8] [21]

RNA dependent RNA polymerase [a]
Identifiers
SymbolRdRP_1
Pfam PF00680
Pfam clan CL0027
InterPro IPR001205
SCOP2 2jlg / SCOPe / SUPFAM
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
RNA-dependent RNA polymerase, eukaryotic-type
Identifiers
SymbolRdRP_euk
Pfam PF05183
InterPro IPR007855
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary
PDB 2j7n
Bunyavirus RNA replicase [b]
Identifiers
SymbolBunya_RdRp
Pfam PF04196
InterPro IPR007322
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

Viruses

Structure and evolution of RdRp in RNA viruses and their superfamilies Fgene-08-00125-g004.jpg
Structure and evolution of RdRp in RNA viruses and their superfamilies

Four superfamilies of viruses cover all RNA-containing viruses with no DNA stage:

Flaviviruses produce a polyprotein from the ssRNA genome. The polyprotein is cleaved to a number of products, one of which is NS5, an RdRp. It possesses short regions and motifs homologous to other RdRps. [22]

RNA replicase found in positive-strand ssRNA viruses are related to each other, forming three large superfamilies. [23] Birnaviral RNA replicase is unique in that it lacks motif C (GDD) in the palm. [24] Mononegaviral RdRp (PDB 5A22) has been automatically classified as similar to (+)−ssRNA RdRps, specifically one from Pestivirus and one from Leviviridae . [25] Bunyaviral RdRp monomer (PDB 5AMQ) resembles the heterotrimeric complex of Orthomyxoviral (Influenza; PDB 4WSB) RdRp. [26]

Since it is a protein universal to RNA-containing viruses, RdRp is a useful marker for understanding their evolution. [27] [28]

Recombination

When replicating its (+)ssRNA genome, the poliovirus RdRp is able to carry out recombination. Recombination appears to occur by a copy choice mechanism in which the RdRp switches (+)ssRNA templates during negative strand synthesis. [29] Recombination frequency is determined in part by the fidelity of RdRp replication. [30] RdRp variants with high replication fidelity show reduced recombination, and low fidelity RdRps exhibit increased recombination. [30] Recombination by RdRp strand switching occurs frequently during replication in the (+)ssRNA plant carmoviruses and tombusviruses. [31]

Intragenic complementation

Sendai virus (family Paramyxoviridae) has a linear, single-stranded, negative-sense, nonsegmented RNA genome. The viral RdRp consists of two virus-encoded subunits, a smaller one P and a larger one L. Testing different inactive RdRp mutants with defects throughout the length of the L subunit in pairwise combinations, restoration of viral RNA synthesis was observed in some combinations. [32] This positive L–L interaction is referred to as intragenic complementation and indicates that the L protein is an oligomer in the viral RNA polymerase complex.[ citation needed ]

Drug therapies

RNA interference

The use of RdRp plays a major role in RNA interference in eukaryotes, a process used to silence gene expression via small interfering RNAs (siRNAs) binding to mRNA rendering them inactive. [36] Eukaryotic RdRp becomes active in the presence of dsRNA, and is less widely distributed than other RNAi components as it lost in some animals, though still found in C. elegans, P. tetraurelia, [37] and plants. [38] This presence of dsRNA triggers the activation of RdRp and RNAi processes by priming the initiation of RNA transcription through the introduction of siRNAs. [37] In C. elegans, siRNAs are integrated into the RNA-induced silencing complex, RISC, which works alongside mRNAs targeted for interference to recruit more RdRps to synthesize more secondary siRNAs and repress gene expression. [39]

See also

Notes

  1. ↑ See Pfam clan for other (+)ssRNA/dsRNA families.
  2. ↑ A (−)ssRNA polymerase.

Related Research Articles

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A DNA virus is a virus that has a genome made of deoxyribonucleic acid (DNA) that is replicated by a DNA polymerase. They can be divided between those that have two strands of DNA in their genome, called double-stranded DNA (dsDNA) viruses, and those that have one strand of DNA in their genome, called single-stranded DNA (ssDNA) viruses. dsDNA viruses primarily belong to two realms: Duplodnaviria and Varidnaviria, and ssDNA viruses are almost exclusively assigned to the realm Monodnaviria, which also includes some dsDNA viruses. Additionally, many DNA viruses are unassigned to higher taxa. Reverse transcribing viruses, which have a DNA genome that is replicated through an RNA intermediate by a reverse transcriptase, are classified into the kingdom Pararnavirae in the realm Riboviria.

<span class="mw-page-title-main">Polymerase</span> Class of enzymes which synthesize nucleic acid chains or polymers

In biochemistry, a polymerase is an enzyme that synthesizes long chains of polymers or nucleic acids. DNA polymerase and RNA polymerase are used to assemble DNA and RNA molecules, respectively, by copying a DNA template strand using base-pairing interactions or RNA by half ladder replication.

<span class="mw-page-title-main">RNA virus</span> Subclass of viruses

An RNA virus is a virus characterized by a ribonucleic acid (RNA) based genome. The genome can be single-stranded RNA (ssRNA) or double-stranded (dsRNA). Notable human diseases caused by RNA viruses include influenza, SARS, MERS, COVID-19, Dengue virus, hepatitis C, hepatitis E, West Nile fever, Ebola virus disease, rabies, polio, mumps, and measles.

<span class="mw-page-title-main">Reverse transcriptase</span> Enzyme which generates DNA

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<span class="mw-page-title-main">Genetic recombination</span> Production of offspring with combinations of traits that differ from those found in either parent

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<span class="mw-page-title-main">Transcription (biology)</span> Process of copying a segment of DNA into RNA

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<span class="mw-page-title-main">DNA polymerase</span> Form of DNA replication

A DNA polymerase is a member of a family of enzymes that catalyze the synthesis of DNA molecules from nucleoside triphosphates, the molecular precursors of DNA. These enzymes are essential for DNA replication and usually work in groups to create two identical DNA duplexes from a single original DNA duplex. During this process, DNA polymerase "reads" the existing DNA strands to create two new strands that match the existing ones. These enzymes catalyze the chemical reaction

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<span class="mw-page-title-main">Hepatitis B virus DNA polymerase</span>

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<span class="mw-page-title-main">Positive-strand RNA virus</span> Class of viruses in the Baltimore classification

Positive-strand RNA viruses are a group of related viruses that have positive-sense, single-stranded genomes made of ribonucleic acid. The positive-sense genome can act as messenger RNA (mRNA) and can be directly translated into viral proteins by the host cell's ribosomes. Positive-strand RNA viruses encode an RNA-dependent RNA polymerase (RdRp) which is used during replication of the genome to synthesize a negative-sense antigenome that is then used as a template to create a new positive-sense viral genome.

<span class="mw-page-title-main">Cap snatching</span> Step in viral RNA transcription

The first step of transcription for some negative, single-stranded RNA viruses is cap snatching, in which the first 10 to 20 residues of a host cell RNA are removed (snatched) and used as the 5′ cap and primer to initiate the synthesis of the nascent viral mRNA. The viral RNA-dependent RNA polymerase (RdRp) can then proceed to transcribe positive-sense viral mRNA using the negative-sense viral RNA as a template. Cap-snatching also explains why some viral mRNA have 5’ terminal extensions of 10-20 nucleotides that are not encoded for in the genome. Examples of viruses that engage in cap-snatching include influenza viruses (Orthomyxoviridae), Lassa virus (Arenaviridae), hantaan virus (Hantaviridae) and rift valley fever virus (Phenuiviridae). Most viruses snatch 15-20 nucleotides except for the families Arenaviridae and Nairoviridae and the genus Thogotovirus (Orthomyxoviridae) which use a shorter strand.

<span class="mw-page-title-main">Negative-strand RNA virus</span> Phylum of viruses

Negative-strand RNA viruses are a group of related viruses that have negative-sense, single-stranded genomes made of ribonucleic acid (RNA). They have genomes that act as complementary strands from which messenger RNA (mRNA) is synthesized by the viral enzyme RNA-dependent RNA polymerase (RdRp). During replication of the viral genome, RdRp synthesizes a positive-sense antigenome that it uses as a template to create genomic negative-sense RNA. Negative-strand RNA viruses also share a number of other characteristics: most contain a viral envelope that surrounds the capsid, which encases the viral genome, −ssRNA virus genomes are usually linear, and it is common for their genome to be segmented.

<i>Riboviria</i> Realm of viruses

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<i>Monodnaviria</i> Realm of viruses

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<i>Orthornavirae</i> Kingdom of viruses

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References

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