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
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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 with no 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 that there is a virus-specific enzyme that could copy RNA from an RNA template and not from a DNA 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 throughout viruses and are even related to telomerase, though the reason for this is an ongoing question as of 2009. [4] The similarity has led to speculation that viral RdRps are ancestral to human telomerase. [5]

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

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

Many eukaryotes also have RdRps and these are involved in RNA interference: these amplify microRNAs and small temporal RNAs and produce double-stranded RNA using small interfering RNAs as primers. [8] In fact these same RdRps that are used in the defense mechanisms can be usurped by RNA viruses for their benefit. [9] Their evolutionary history has been reviewed. [10]

Replication process

RdRp differs from DNA dependent RNA polymerase as it works to catalyze the synthesis of an RNA strand complementary to a given RNA template, rather than using a DNA template. The RNA replication process is a four-step mechanism, as described.

  1. Nucleoside triphosphate (NTP) binding – initially, the RdRp presents with a vacant active site in which an NTP binds, complementary to the corresponding nucleotide on the template strand. Correct NTP binding causes the RdRp to undergo a conformational change. [11]
  2. Active site closure – the conformational change, initiated by the correct NTP binding, results in the restriction of active site access and produces a catalytically competent state. [11]
  3. Phosphodiester bond formation – two Mg2+ ions are present in the catalytically active state and arrange themselves in such a way around the newly synthesized RNA chain that the substrate NTP is able to undergo a phosphatidyl transfer and form a phosphodiester bond with the newly synthesized chain. [12] Without the use of these Mg2+ ions, the active site is no longer catalytically stable and the RdRp complex changes to an open conformation. [12]
  4. Translocation – once the active site is open, the RNA template strand is able to move by one position through the RdRp protein complex and continue chain elongation by binding a new NTP, unless otherwise specified by the template. [11]

RNA synthesis can be performed by means of 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 nucleoside triphosphate (NTP) to the 3'-OH of the first initiating NTP. [13] During the following so-called 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, it has been shown that RdRp termination is sequence-independent. [14]

One major drawback of RNA-dependent RNA polymerase replication is the immense error rate during transcription. [13] RdRps are known to have a lack of fidelity on the order of 104 nucleotides, which is thought to be a direct result of its insufficient proofreading abilities. [13] This high rate of variation is favored in viral genomes as it allows for the pathogen to overcome defenses developed by hosts 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 RNA-directed RNA polymerases, along with many single-subunit DNA-directed polymerases, 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 among all of these enzymes. 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 a number of conserved amino acid residues.[ citation needed ]

Eukaryotic RNA interference requires a cellular RNA-dependent RNA polymerase (c RdRp). Unlike the "hand" polymerases, they resemble simplified multi-subunit DNA-dependent RNA polymerases (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 [lower-alpha 1]
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 [lower-alpha 2]
Identifiers
SymbolBunya_RdRp
Pfam PF04196
InterPro IPR007322
Available protein structures:
Pfam   structures / ECOD  
PDB RCSB PDB; PDBe; PDBj
PDBsum structure summary

In 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

There are 4 superfamilies of viruses that 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 RNA-dependent RNA polymerase. This RNA-directed RNA polymerase possesses a number of short regions and motifs homologous to other RNA-directed RNA polymerases. [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] The overall structural evolution of viral RdRps has been reviewed. [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 also 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. When different inactive RdRp mutants with defects throughout the length of the L subunit where tested 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 RNA-dependent RNA polymerase 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 a less widely distributed compared to other RNAi components as it lost in some animals, though still found in C. elegans and 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 into the system. [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

<span class="mw-page-title-main">DNA virus</span> Virus that has DNA as its genetic material

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—other than a retrovirus—that has ribonucleic acid (RNA) as its genetic material. The nucleic acid is usually single-stranded RNA (ssRNA) but it may be double-stranded (dsRNA). Notable human diseases caused by RNA viruses include the common cold, 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

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 viruses such as HIV and hepatitis B 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.

<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

Transcription is the process of copying a segment of DNA into RNA. The segments of DNA transcribed into RNA molecules that can encode proteins produce messenger RNA (mRNA). Other segments of DNA are transcribed into RNA molecules called non-coding RNAs (ncRNAs).

<span class="mw-page-title-main">RNA polymerase</span> Enzyme that synthesizes RNA from DNA

In molecular biology, RNA polymerase, or more specifically DNA-directed/dependent RNA polymerase (DdRP), is an enzyme that catalyzes the chemical reactions that synthesize RNA from a DNA template.

<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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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.

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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>

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 replicate the negative-sense genome from the positive-sense 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

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, as well as 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>Monodnaviria</i> Realm of viruses

Monodnaviria is a realm of viruses that includes all single-stranded DNA viruses that encode an endonuclease of the HUH superfamily that initiates rolling circle replication of the circular viral genome. Viruses descended from such viruses are also included in the realm, including certain linear single-stranded DNA (ssDNA) viruses and circular double-stranded DNA (dsDNA) viruses. These atypical members typically replicate through means other than rolling circle replication.

<i>Orthornavirae</i> Kingdom of viruses

Orthornavirae is a kingdom of viruses that have genomes made of ribonucleic acid (RNA), including genes which encode an RNA-dependent RNA polymerase (RdRp). The RdRp is used to transcribe the viral RNA genome into messenger RNA (mRNA) and to replicate the genome. Viruses in this kingdom share a number of characteristics which promote rapid evolution, including high rates of genetic mutation, recombination, and reassortment.

<span class="mw-page-title-main">Nsp12</span> Protein in the Coronavirus genome

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References

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