Replication of the SARS-CoV-2 genome

Stable Identifier
R-HSA-9694686
Type
Pathway
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
ReviewStatus
5/5
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Replication of the SARS-CoV-2 genome
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This COVID-19 pathway has been created by a combination of computational inference from SARS-CoV-1 data (https://reactome.org/documentation/inferred-events) and manual curation, as described in the summation for the overall SARS-CoV-2 infection pathway. Steps of SARS-CoV-2 genome replication that have been studied directly include binding of the replication transcription complex (RTC) to the RNA template and the polymerase activity of nsp12 (Hillen et al. 2020, Wang et al. 2020, Yin et al. 2020), helicase activity of nsp13 (Chen et al. 2020, Ji et al. 2020, Shu et al. 2020), capping activity of nsp16 (Viswanathan et al. 2020), and polyadenylation of SARS-CoV-2 genomic RNA (Kim et al. 2020). Replication is localized in double-membrane vesicles (DMVs) that are created by distortion of ER membranes (Cortese et al, 2020; Snijder et al, 2020). One host factor needed for formation of these replication organelles is phosphatidic acid (Tabata et al, 2021). Other steps have been inferred from previous studies in SARS-CoV-1 and related coronaviruses.

The plus strand RNA genome of the human SARS coronavirus 1 (SARS-CoV-1) is replicated by the viral replication-transcription complex (RTC) composed of nonstructural proteins nsp3-nsp16, encoded by open reading frames ORF1a and ORF1b. Two RTC proteins, nsp8 and nsp12, possess 5'-3' RNA-dependent RNA polymerase activity. nsp12 is the main RNA polymerase, while nsp8 is thought to act as an RNA primase. nsp14 acts as a 3'-5' exonuclease, increasing the fidelity of the RTC. nsp14 also has the RNA capping activity and, in concert with nsp16, it caps viral plus strand and minus strand genomic and subgenomic RNAs, which confers stability to viral RNAs by enabling them to escape interferon-mediated innate immune responses of the host. nsp13 is an RNA helicase which is thought to melt secondary structures in the genomic RNA during replication and transcription. The plus strand genomic RNA is first used to synthesize the minus strand genomic RNA complement, which is subsequently used as a template for synthesis of plus strand viral RNA genomes that are packaged into mature virions. For review, please refer to Yang and Leibowitz 2015, Snijder et al. 2016, Fung and Liu 2019.
Literature References
PubMed ID Title Journal Year
32484220 Discovery of G-quadruplex-forming sequences in SARS-CoV-2

Kwok, CK, Juhas, M, Zhang, Y, Tsang, CM, Ji, D, Li, Y

Brief. Bioinformatics 2020
34907161 Convergent use of phosphatidic acid for hepatitis C virus and SARS-CoV-2 replication organelle formation

Tran, CS, Superti-Furga, G, Beneke, J, Stahl, Y, Kaderali, L, Müller, AC, Prasad, V, Hörmann, K, Twu, WI, Lee, JY, Pham, MT, Lohmann, V, V'kovski, P, Bartenschlager, R, Zitzmann, C, Cerikan, B, Lüchtenborg, C, Thiel, V, Joecks, S, Neufeldt, CJ, Cortese, M, Erfle, H, Tabata, K, Brugger, B, Haselmann, U, Paul, D

Nat Commun 2021
27712628 The Nonstructural Proteins Directing Coronavirus RNA Synthesis and Processing

Ziebuhr, J, Snijder, EJ, Decroly, E

Adv. Virus Res. 2016
32783916 Structural Basis for Helicase-Polymerase Coupling in the SARS-CoV-2 Replication-Transcription Complex

Maruthi, K, Chait, BT, Malone, B, Llewellyn, E, Campbell, EA, Vatandaslar, H, Grasso, M, Shelton, PMM, Olinares, PDB, Kapoor, TM, Eng, ET, Chen, J, Darst, SA

Cell 2020
33245857 Integrative Imaging Reveals SARS-CoV-2-Induced Reshaping of Subcellular Morphologies

Schwab, Y, Mocaer, K, Gross, V, Oorschot, VMJ, Ruggieri, A, Boulant, S, Templin, RM, Romero-Brey, I, Chatel-Chaix, L, Boermel, M, Hennies, J, Lee, JY, Beckwith, MS, Köhrer, S, Schieber, NL, Bartenschlager, R, Mizzon, G, Ronchi, P, Laketa, V, Schorb, M, Stanifer, M, Horvat, NK, Cerikan, B, Frankish, J, Neufeldt, CJ, Tischer, C, Pape, C, Cortese, M, Santarella-Mellwig, R

Cell Host Microbe 2020
32358203 Structural basis for inhibition of the RNA-dependent RNA polymerase from SARS-CoV-2 by remdesivir

Jiang, Y, Wang, X, Shen, DD, Su, H, Tao, SC, Xie, YC, Zhang, Y, Gao, M, Jiang, H, Mao, C, Xu, HE, Zhang, S, Shen, J, Zhou, F, Luan, X, Jiang, HW, Yin, W, Zhao, W, Xu, Y, Shen, Q, Tian, G, Chang, S

Science 2020
32511245 A unifying structural and functional model of the coronavirus replication organelle: Tracking down RNA synthesis

Maier, HJ, Limpens, RWAL, de Jong, AWM, Koster, AJ, Faas, FFGA, de Wilde, AH, Zevenhoven-Dobbe, JC, Bárcena, M, Snijder, EJ

PLoS Biol 2020
25736566 The structure and functions of coronavirus genomic 3' and 5' ends

Leibowitz, JL, Yang, D

Virus Res. 2015
32330414 The Architecture of SARS-CoV-2 Transcriptome

Kim, JW, Kim, D, Lee, JY, Yang, JS, Chang, H, Kim, VN

Cell 2020
32500504 SARS-Coronavirus-2 Nsp13 Possesses NTPase and RNA Helicase Activities That Can Be Inhibited by Bismuth Salts

Wu, D, Zhang, X, Shu, T, Qiu, Y, Zhang, DY, Huang, M, Zhou, X, Han, Y, Mu, J, Ren, Y, Wang, R

Virol Sin 2020
32709886 Structural basis of RNA cap modification by SARS-CoV-2

Dai, N, Martínez-Sobrido, L, Kovalskyy, D, Chan, SH, Oladunni, F, Qi, S, Park, JG, Misra, A, Gupta, YK, Viswanathan, T, Hromas, RA, Arya, S

Nat Commun 2020
32438371 Structure of replicating SARS-CoV-2 polymerase

Dienemann, C, Tegunov, D, Cramer, P, Farnung, L, Kokic, G, Hillen, HS

Nature 2020
31226023 Human Coronavirus: Host-Pathogen Interaction

Fung, TS, Liu, DX

Annu. Rev. Microbiol. 2019
32526208 Structural Basis for RNA Replication by the SARS-CoV-2 Polymerase

Gong, P, Lou, Z, Gao, Y, Zhu, C, Yang, H, Yan, L, Liu, Z, Xu, W, Yang, X, Wang, Q, Liu, F, Rao, Z, Huang, Y, Zhu, Y, Wu, J, Yang, X, Liu, Q, Ji, W, Ge, J, Gao, H, Jiang, B, Fang, X, Wang, H, Guddat, LW, Sun, Q, Mu, A

Cell 2020
Participants
Events
Participates
as an event of
Disease
Name Identifier Synonyms
COVID-19 DOID:0080600 2019 Novel Coronavirus (2019-nCoV), Wuhan seafood market pneumonia virus infection, 2019-nCoV infection, Wuhan coronavirus infection
Authored
Orlic-Milacic, M  (2020-08-12)
Senff-Ribeiro, A  (2020-08-12)
Reviewed
Acencio, ML  (2020-09-09)
Created
Cook, J  (2020-07-07)
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