{{Short description|Enzyme that synthesizes RNA from an RNA template}} {{cs1 config|name-list-style=vanc|display-authors=6}} {{Distinguish|DNA-dependent RNA polymerase}} {{Infobox enzyme | Name = RNA-dependent RNA polymerase | EC_number = 2.7.7.48 | CAS_number = 9026-28-2 | GO_code = GO:0003968 | image = HCV NS5B RdRP stalled 4WTG.png | caption = Stalled Hepatitis C virus RNA replicase (NS5B), in complex with sofosbuvir (PDB 4WTG). |name=}}
'''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 (DdRP), which all organisms use to catalyze the transcription of RNA from a DNA template.
RdRp is an essential protein encoded in the genomes of most RNA-containing viruses that lack a DNA stage.<ref name="pmid2759231">{{cite journal | vauthors = Koonin EV, Gorbalenya AE, Chumakov KM | title = Tentative identification of RNA-dependent RNA polymerases of dsRNA viruses and their relationship to positive strand RNA viral polymerases | journal = FEBS Letters | volume = 252 | issue = 1–2 | pages = 42–46 | date = July 1989 | pmid = 2759231 | doi = 10.1016/0014-5793(89)80886-5 | s2cid = 36482110 | doi-access = | bibcode = 1989FEBSL.252...42K }}</ref><ref name="pmid8709232">{{cite journal | vauthors = Zanotto PM, Gibbs MJ, Gould EA, Holmes EC | title = A reevaluation of the higher taxonomy of viruses based on RNA polymerases | journal = Journal of Virology | volume = 70 | issue = 9 | pages = 6083–6096 | date = September 1996 | pmid = 8709232 | pmc = 190630 | doi = 10.1128/JVI.70.9.6083-6096.1996 }}</ref> 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 Picornaviruses 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.<ref>{{cite journal | vauthors = Baltimore D, Franklin RM | title = A New Ribonucleic Acid Polymerase Appearing after Mengovirus Infection of L-Cells | journal = The Journal of Biological Chemistry | volume = 238 | issue = 10 | pages = 3395–3400 | date = October 1963 | pmid = 14085393 | doi = 10.1016/S0021-9258(18)48679-6 | doi-access = free }}</ref>
== Distribution ==
{{multiple image |width = 220 |direction = vertical |align = right |image1=Viruses-07-02829-g001a.png |image2=Viruses-07-02829-g001b.webp |caption1= |caption2= 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.<ref name="pmid16163346">{{cite journal | vauthors = Suttle CA | title = Viruses in the sea | journal = Nature | volume = 437 | issue = 7057 | pages = 356–361 | date = September 2005 | pmid = 16163346 | doi = 10.1038/nature04160 | s2cid = 4370363 | bibcode = 2005Natur.437..356S }}</ref> The similarity led to speculation that viral RdRps are ancestral to human telomerase.<ref>{{cite journal | vauthors = Weiner AM | title = Eukaryotic nuclear telomeres: molecular fossils of the RNP world? | journal = Cell | volume = 52 | issue = 2 | pages = 155–158 | date = January 1988 | pmid = 2449282 | doi = 10.1016/0092-8674(88)90501-6 | s2cid = 11491076 }}</ref>
The most famous example of RdRp is in poliovirus. 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.<ref>{{Cite book | vauthors = Dawkins R | url= https://terebess.hu/keletkultinfo/The_Blind_Watchmaker.pdf |title=The Blind Watchmaker |publisher=W.W. Norton&Company |year=1996 |isbn=978-0-393-35309-9 |edition=3d |location=London |publication-date=1996 |pages=129 |language=en}}</ref>
Many RdRps associate tightly with membranes making them difficult to study. The best-known RdRps are polioviral 3Dpol, vesicular stomatitis virus L,<ref>{{cite journal | vauthors = Timm C, Gupta A, Yin J | title = Robust kinetics of an RNA virus: Transcription rates are set by genome levels | journal = Biotechnology and Bioengineering | volume = 112 | issue = 8 | pages = 1655–1662 | date = August 2015 | pmid = 25726926 | pmc = 5653219 | doi = 10.1002/bit.25578 | bibcode = 2015BiotB.112.1655T }}</ref> 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.<ref name="pmid12553882">{{cite journal | vauthors = Iyer LM, Koonin EV, Aravind L | title = Evolutionary connection between the catalytic subunits of DNA-dependent RNA polymerases and eukaryotic RNA-dependent RNA polymerases and the origin of RNA polymerases | journal = BMC Structural Biology | volume = 3 | article-number = 1 | date = January 2003 | pmid = 12553882 | pmc = 151600 | doi = 10.1186/1472-6807-3-1 | doi-access = free }}</ref> These RdRps are used in defense mechanisms and can be appropriated by RNA viruses.<ref>{{cite journal | vauthors = Tan FL, Yin JQ | title = RNAi, a new therapeutic strategy against viral infection | journal = Cell Research | volume = 14 | issue = 6 | pages = 460–466 | date = December 2004 | pmid = 15625012 | pmc = 7092015 | doi = 10.1038/sj.cr.7290248 }}</ref> Their evolutionary history predates the divergence of major eukaryotic groups.<ref>{{cite journal | vauthors = Zong J, Yao X, Yin J, Zhang D, Ma H | title = Evolution of the RNA-dependent RNA polymerase (RdRP) genes: duplications and possible losses before and after the divergence of major eukaryotic groups | journal = Gene | volume = 447 | issue = 1 | pages = 29–39 | date = November 2009 | pmid = 19616606 | doi = 10.1016/j.gene.2009.07.004 }}</ref>
== 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:
* 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.<ref name=":0">{{cite journal | vauthors = Wu J, Gong P | title = Visualizing the Nucleotide Addition Cycle of Viral RNA-Dependent RNA Polymerase | journal = Viruses | volume = 10 | issue = 1 | page = 24 | date = January 2018 | pmid = 29300357 | pmc = 5795437 | doi = 10.3390/v10010024 | doi-access = free }}</ref> * 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.<ref name=":0" /> * Phosphodiester bond formation – two Mg<sup>2+</sup> ions are present in the catalytically active state and arrange themselves around the newly synthesized RNA chain such that the substrate NTP undergoes a phosphatidyl transfer and forms a phosphodiester bond with the new chain.<ref name=":1">{{cite journal | vauthors = Shu B, Gong P | title = Structural basis of viral RNA-dependent RNA polymerase catalysis and translocation | journal = Proceedings of the National Academy of Sciences of the United States of America | volume = 113 | issue = 28 | pages = E4005–E4014 | date = July 2016 | pmid = 27339134 | pmc = 4948327 | doi = 10.1073/pnas.1602591113 | doi-access = free | bibcode = 2016PNAS..113E4005S }}</ref> Without the use of these Mg<sup>2+</sup> ions, the active site is no longer catalytically stable and the RdRp complex changes to an open conformation.<ref name=":1" /> * Translocation – once the active site is open, the RNA template strand moves by one position through the RdRp protein complex and continues chain elongation by binding a new NTP, unless otherwise specified by the template.<ref name=":0" />
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.<ref name=":2" /> The ''de novo'' initiation consists in the addition of a NTP to the 3'-OH of the first initiating NTP.<ref name=":2">{{cite journal | vauthors = Venkataraman S, Prasad BV, Selvarajan R | title = RNA Dependent RNA Polymerases: Insights from Structure, Function and Evolution | journal = Viruses | volume = 10 | issue = 2 | page = 76 | date = February 2018 | pmid = 29439438 | pmc = 5850383 | doi = 10.3390/v10020076 | doi-access = free }}</ref> 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.<ref>{{cite journal | vauthors = Adkins S, Stawicki SS, Faurote G, Siegel RW, Kao CC | title = Mechanistic analysis of RNA synthesis by RNA-dependent RNA polymerase from two promoters reveals similarities to DNA-dependent RNA polymerase | journal = RNA | volume = 4 | issue = 4 | pages = 455–470 | date = April 1998 | pmid = 9630251 | pmc = 1369631 }}</ref>
One major drawback of RNA-dependent RNA polymerase replication is the transcription error rate.<ref name=":2" /> RdRps lack fidelity on the order of 10<sup>4</sup> nucleotides, which is thought to be a direct result of inadequate proofreading.<ref name=":2" /> 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.<ref>{{cite journal | vauthors = Fitzsimmons WJ, Woods RJ, McCrone JT, Woodman A, Arnold JJ, Yennawar M, Evans R, Cameron CE, Lauring AS | title = A speed-fidelity trade-off determines the mutation rate and virulence of an RNA virus | journal = PLOS Biology | volume = 16 | issue = 6 | article-number = e2006459 | date = June 2018 | pmid = 29953453 | pmc = 6040757 | doi = 10.1371/journal.pbio.2006459 | doi-access = free }}</ref>
== Structure == thumb|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.<ref name="pmid9309225">{{cite journal | vauthors = Hansen JL, Long AM, Schultz SC | title = Structure of the RNA-dependent RNA polymerase of poliovirus | journal = Structure | volume = 5 | issue = 8 | pages = 1109–1122 | date = August 1997 | pmid = 9309225 | doi = 10.1016/S0969-2126(97)00261-X | doi-access = free }}</ref> 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 Mg<sup>2+</sup> and/or Mn<sup>2+</sup>. 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.<ref name="pmid10827187">{{cite journal | vauthors = Gohara DW, Crotty S, Arnold JJ, Yoder JD, Andino R, Cameron CE | title = Poliovirus RNA-dependent RNA polymerase (3Dpol): structural, biochemical, and biological analysis of conserved structural motifs A and B | journal = The Journal of Biological Chemistry | volume = 275 | issue = 33 | pages = 25523–25532 | date = August 2000 | pmid = 10827187 | doi = 10.1074/jbc.M002671200 | doi-access = free }}</ref> The domain organization<ref name="pmid9878607">{{cite journal | vauthors = O'Reilly EK, Kao CC | title = Analysis of RNA-dependent RNA polymerase structure and function as guided by known polymerase structures and computer predictions of secondary structure | journal = Virology | volume = 252 | issue = 2 | pages = 287–303 | date = December 1998 | pmid = 9878607 | doi = 10.1006/viro.1998.9463 | doi-access = free }}</ref> 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.{{cn|date=October 2022}}
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 ({{UniProt|Q9Y7G6}}) in ''Neurospora crassa'', which has both barrels in the same chain,<ref name=qde1-mono>{{cite journal | vauthors = Sauguet L | title = The Extended "Two-Barrel" Polymerases Superfamily: Structure, Function and Evolution | journal = Journal of Molecular Biology | volume = 431 | issue = 20 | pages = 4167–4183 | date = September 2019 | pmid = 31103775 | doi = 10.1016/j.jmb.2019.05.017 | doi-access = free }}</ref> is an example of such a c RdRp enzyme.<ref name="pmid21233849">{{cite journal | vauthors = Werner F, Grohmann D | title = Evolution of multisubunit RNA polymerases in the three domains of life | journal = Nature Reviews. Microbiology | volume = 9 | issue = 2 | pages = 85–98 | date = February 2011 | pmid = 21233849 | doi = 10.1038/nrmicro2507 | s2cid = 30004345 }}</ref> Bacteriophage homologs of c RdRp, including the similarly single-chain DdRp yonO ({{UniProt|O31945}}), appear to be closer to c RdRps than DdRPs are.<ref name="pmid12553882"/><ref>{{cite journal | vauthors = Forrest D, James K, Yuzenkova Y, Zenkin N | title = Single-peptide DNA-dependent RNA polymerase homologous to multi-subunit RNA polymerase | journal = Nature Communications | volume = 8 | article-number = 15774 | date = June 2017 | pmid = 28585540 | pmc = 5467207 | doi = 10.1038/ncomms15774 | bibcode = 2017NatCo...815774F }}</ref>
{| |- valign="top" |{{Infobox protein family | Symbol = RdRP_1 | Name = RNA dependent RNA polymerase{{efn|See Pfam clan for other (+)ssRNA/dsRNA families.}} | Pfam = PF00680 | Pfam_clan = CL0027 | InterPro = IPR001205 | SCOP = 2jlg }} |{{Pfam box |Pfam=PF05183|Symbol=RdRP_euk|InterPro=IPR007855|Name=RNA-dependent RNA polymerase, eukaryotic-type|PDB=2j7n}} |{{Pfam box |Symbol = Bunya_RdRp | Name = Bunyavirus RNA replicase{{efn|A (−)ssRNA polymerase.}} | InterPro = IPR007322 | Pfam=PF04196}} |}
==Viruses==
thumb|Structure and evolution of RdRp in RNA viruses and their superfamilies
Four superfamilies of viruses cover all RNA-containing viruses with no DNA stage: * Viruses containing positive-strand RNA or double-strand RNA, except retroviruses and ''Birnaviridae'' ** All positive-strand RNA eukaryotic viruses with no DNA stage, such as ''Coronaviridae'' ** All RNA-containing bacteriophages; the two families of RNA-containing bacteriophages are ''Fiersviridae'' (positive ssRNA phages) and ''Cystoviridae'' (dsRNA phages) ** dsRNA virus family ''Reoviridae'', ''Totiviridae'', ''Hypoviridae'', ''Partitiviridae''<!-- Need more info; the 1991 article does not cover these --> * ''Mononegavirales'' (negative-strand RNA viruses with non-segmented genomes; {{InterPro|IPR016269}}) * Negative-strand RNA viruses with segmented genomes ({{InterPro|IPR007099}}), such as orthomyxoviruses and bunyaviruses * dsRNA virus family ''Birnaviridae'' ({{InterPro|IPR007100}})
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.<ref name="pmid8607261">{{cite journal | vauthors = Tan BH, Fu J, Sugrue RJ, Yap EH, Chan YC, Tan YH | title = Recombinant dengue type 1 virus NS5 protein expressed in Escherichia coli exhibits RNA-dependent RNA polymerase activity | journal = Virology | volume = 216 | issue = 2 | pages = 317–325 | date = February 1996 | pmid = 8607261 | doi = 10.1006/viro.1996.0067 | doi-access = free }}</ref>
RNA replicase found in positive-strand ssRNA viruses are related to each other, forming three large superfamilies.<ref>{{cite journal | vauthors = Koonin EV | title = The phylogeny of RNA-dependent RNA polymerases of positive-strand RNA viruses | journal = The Journal of General Virology | volume = 72 ( Pt 9) | issue = 9 | pages = 2197–2206 | date = September 1991 | pmid = 1895057 | doi = 10.1099/0022-1317-72-9-2197 | doi-access = free }}</ref> Birnaviral RNA replicase is unique in that it lacks motif C (GDD) in the palm.<ref name="pmid12069523">{{cite journal | vauthors = Shwed PS, Dobos P, Cameron LA, Vakharia VN, Duncan R | title = Birnavirus VP1 proteins form a distinct subgroup of RNA-dependent RNA polymerases lacking a GDD motif | journal = Virology | volume = 296 | issue = 2 | pages = 241–250 | date = May 2002 | pmid = 12069523 | doi = 10.1006/viro.2001.1334 | doi-access = free }}</ref> Mononegaviral RdRp (PDB 5A22) has been automatically classified as similar to (+)−ssRNA RdRps, specifically one from ''Pestivirus'' and one from ''Leviviridae''.<ref>[https://www.rcsb.org/pdb/explore/structureCluster.do?structureId=5A22 Structural Similarities for the Entities in PDB 5A22] {{Webarchive|url=https://web.archive.org/web/20190403215442/https://www.rcsb.org/pdb/explore/structureCluster.do?structureId=5A22 |date=2019-04-03 }}.</ref> Bunyaviral RdRp monomer (PDB 5AMQ) resembles the heterotrimeric complex of Orthomyxoviral (Influenza; PDB 4WSB) RdRp.<ref>{{cite journal | vauthors = Gerlach P, Malet H, Cusack S, Reguera J | title = Structural Insights into Bunyavirus Replication and Its Regulation by the vRNA Promoter | journal = Cell | volume = 161 | issue = 6 | pages = 1267–1279 | date = June 2015 | pmid = 26004069 | pmc = 4459711 | doi = 10.1016/j.cell.2015.05.006 }}</ref>
[[File:MBio.02329-18.F1.large.jpg|thumb|2018 phylogenetic tree with phylum branches highlighted. ''Negarnaviricota'' (brown), ''Duplornaviricota'' (green), ''Kitrinoviricota'' (pink), ''Pisuviricota'' (blue), and ''Lenarviricota'' (yellow)<ref name=Wolf18/>]] Since it is a protein universal to RNA-containing viruses, RdRp is a useful marker for understanding their evolution.<ref name=Wolf18>{{cite journal | vauthors = Wolf YI, Kazlauskas D, Iranzo J, Lucía-Sanz A, Kuhn JH, Krupovic M, Dolja VV, Koonin EV | title = Origins and Evolution of the Global RNA Virome | journal = mBio | volume = 9 | issue = 6 | date = November 2018 | article-number = e02329-18 | pmid = 30482837 | pmc = 6282212 | doi = 10.1128/mBio.02329-18 | doi-access = free}}</ref><ref>{{cite journal | vauthors = Černý J, Černá Bolfíková B, Valdés JJ, Grubhoffer L, Růžek D | title = Evolution of tertiary structure of viral RNA dependent polymerases | journal = PLOS ONE | volume = 9 | issue = 5 | article-number = e96070 | date = 2014 | pmid = 24816789 | pmc = 4015915 | doi = 10.1371/journal.pone.0096070 | doi-access = free | bibcode = 2014PLoSO...996070C }}</ref> The RdRP-bearing viruses are united into the taxon Orthornavirae.
===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.<ref name="pmid3021340">{{cite journal | vauthors = Kirkegaard K, Baltimore D | title = The mechanism of RNA recombination in poliovirus | journal = Cell | volume = 47 | issue = 3 | pages = 433–443 | date = November 1986 | pmid = 3021340 | pmc = 7133339 | doi = 10.1016/0092-8674(86)90600-8 }}</ref> Recombination frequency is determined in part by the fidelity of RdRp replication.<ref name = Woodman2016>{{cite journal | vauthors = Woodman A, Arnold JJ, Cameron CE, Evans DJ | title = Biochemical and genetic analysis of the role of the viral polymerase in enterovirus recombination | journal = Nucleic Acids Research | volume = 44 | issue = 14 | pages = 6883–6895 | date = August 2016 | pmid = 27317698 | pmc = 5001610 | doi = 10.1093/nar/gkw567 }}</ref> RdRp variants with high replication fidelity show reduced recombination, and low fidelity RdRps exhibit increased recombination.<ref name = Woodman2016/> Recombination by RdRp strand switching occurs frequently during replication in the (+)ssRNA plant carmoviruses and tombusviruses.<ref name="pmid14581540">{{cite journal | vauthors = Cheng CP, Nagy PD | title = Mechanism of RNA recombination in carmo- and tombusviruses: evidence for template switching by the RNA-dependent RNA polymerase in vitro | journal = Journal of Virology | volume = 77 | issue = 22 | pages = 12033–12047 | date = November 2003 | pmid = 14581540 | pmc = 254248 | doi = 10.1128/jvi.77.22.12033-12047.2003 }}</ref>
===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.<ref name="pmid12504565">{{cite journal | vauthors = Smallwood S, Cevik B, Moyer SA | title = Intragenic complementation and oligomerization of the L subunit of the sendai virus RNA polymerase | journal = Virology | volume = 304 | issue = 2 | pages = 235–245 | date = December 2002 | pmid = 12504565 | doi = 10.1006/viro.2002.1720 | doi-access = free }}</ref> 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.{{cn|date=October 2022}}
== Drug therapies == * RdRps can be used as drug targets for viral pathogens as their function is not necessary for eukaryotic survival. By inhibiting RdRp function, new RNAs cannot be replicated from an RNA template strand, however, DNA-dependent RNA polymerase remains functional. * Some antiviral drugs against Hepatitis C and COVID-19 specifically target RdRp. These include Sofosbuvir and Ribavirin against Hepatitis C<ref>{{cite journal | vauthors = Waheed Y, Bhatti A, Ashraf M | title = RNA dependent RNA polymerase of HCV: a potential target for the development of antiviral drugs | journal = Infection, Genetics and Evolution | volume = 14 | pages = 247–257 | date = March 2013 | pmid = 23291407 | doi = 10.1016/j.meegid.2012.12.004 | bibcode = 2013InfGE..14..247W }}</ref> and remdesivir, an FDA approved drug against COVID-19 * GS-441524 triphosphate is a substrate for RdRp, but not mammalian polymerases. It results in premature chain termination and inhibition of viral replication. GS-441524 triphosphate is the biologically active form of remdesivir. Remdesivir is classified as a nucleotide analog that inhibits RdRp function by covalently binding to and interrupting termination of the nascent RNA through early or delayed termination or preventing further elongation of the RNA polynucleotide.<ref>{{cite journal | vauthors = Yin W, Mao C, Luan X, Shen DD, Shen Q, Su H, Wang X, Zhou F, Zhao W, Gao M, Chang S, Xie YC, Tian G, Jiang HW, Tao SC, Shen J, Jiang Y, Jiang H, Xu Y, Zhang S, Zhang Y, Xu HE | title = Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir | journal = Science | volume = 368 | issue = 6498 | pages = 1499–1504 | date = June 2020 | pmid = 32358203 | pmc = 7199908 | doi = 10.1126/science.abc1560 | bibcode = 2020Sci...368.1499Y }}</ref><ref>{{cite journal | vauthors = Malin JJ, Suárez I, Priesner V, Fätkenheuer G, Rybniker J | title = Remdesivir against COVID-19 and Other Viral Diseases | journal = Clinical Microbiology Reviews | volume = 34 | issue = 1 | date = December 2020 | article-number = e00162-20 | pmid = 33055231 | pmc = 7566896 | doi = 10.1128/CMR.00162-20 }}</ref> This early termination leads to nonfunctional RNA that gets degraded through normal cellular processes.
== 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.<ref>{{cite journal | vauthors = Simaan JA, Aviado DM | title = Hemodynamic effects of aerosol propellants. II. Pulmonary circulation in the dog | journal = Toxicology | volume = 5 | issue = 2 | pages = 139–146 | date = November 1975 | pmid = 1873 | doi = 10.1016/0300-483x(75)90110-9 | bibcode = 1975Toxgy...5..139S }}</ref> 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,''<ref name=":3">{{cite journal | vauthors = Marker S, Le Mouël A, Meyer E, Simon M | title = Distinct RNA-dependent RNA polymerases are required for RNAi triggered by double-stranded RNA versus truncated transgenes in Paramecium tetraurelia | journal = Nucleic Acids Research | volume = 38 | issue = 12 | pages = 4092–4107 | date = July 2010 | pmid = 20200046 | pmc = 2896523 | doi = 10.1093/nar/gkq131 }}</ref> and plants.<ref>{{cite journal | vauthors = Willmann MR, Endres MW, Cook RT, Gregory BD | title = The Functions of RNA-Dependent RNA Polymerases in Arabidopsis | journal = The Arabidopsis Book | volume = 9 | article-number = e0146 | date = July 2011 | pmid = 22303271 | pmc = 3268507 | doi = 10.1199/tab.0146 }}</ref> This presence of dsRNA triggers the activation of RdRp and RNAi processes by priming the initiation of RNA transcription through the introduction of siRNAs.<ref name=":3" /> 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.<ref>{{cite journal | vauthors = Zhang C, Ruvkun G | title = New insights into siRNA amplification and RNAi | journal = RNA Biology | volume = 9 | issue = 8 | pages = 1045–1049 | date = August 2012 | pmid = 22858672 | pmc = 3551858 | doi = 10.4161/rna.21246 }}</ref>
== See also == * Spiegelman's Monster * NS5B inhibitor
==Notes== {{notelist}}
== References == {{Reflist}}
== External links == * {{MeshName|RNA+Replicase}} * {{EC number|2.7.7.48}}
{{Kinases}} {{Enzymes}} {{Gene expression}} {{Portal bar|Biology|border=no}}
{{InterPro content|IPR000208}}
{{DEFAULTSORT:Rna-Dependent Rna Polymerase}} Category:Gene expression Category:RNA Category:EC 2.7.7