nsp14 acts as a 3'-to-5' exonuclease to remove misincorporated nucleotides from nascent RNA

Stable Identifier
R-HSA-9694632
Type
Reaction [transition]
Species
Homo sapiens
Related Species
Severe acute respiratory syndrome coronavirus 2
Compartment
cytosol, double membrane vesicle viral factory outer membrane
ReviewStatus
5/5
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nsp14 acts as a 3'-to-5' exonuclease to remove misincorporated nucleotides from nascent RNA
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In human SARS coronavirus 2 (SARS-CoV-2) nsp14 is essential for SARS-Cov-2 viability (Ogando et al, 2020). Mutations in nsp14 lead to an increased mutation load in the replicated viral genome, ultimately increasing genomic diversity (Eskier et al, 2020; Takada et al, 2020). The complex of nsp14 with nsp10 has 3'-5' exonuclease activity that is applied to mismatched nucleotides in newly replicated viral RNA (Saramago et al, 2021; Lin et al, 2021; Liu et al, 2021; Moeller et al, 2021; Ma et al, 2021). Binding to nsp10 increases the exonuclease activity of nsp14 260-fold (Riccio et al, 2022).

In SARS-CoV-1 nsp14 acts as 3'-5' exonuclease (Minskaia et al. 2006, Chen et al. 2007) that preferentially excises mismatched nucleotides from double stranded RNA (Minskaia et al. 2006, Bouvet et al. 2012). Binding to nsp10 increases the exonuclease activity of nsp14 (Bouvet et al. 2012, Subissi et al. 2014, Bouvet et al. 2014). nsp14 increases the fidelity of SARS-CoV-1 replication by the nsp12 RNA-dependent RNA polymerase by 21-fold (Eckerle et al. 2010).
Literature References
PubMed ID Title Journal Year
33956156 Crystal structure of SARS-CoV-2 nsp10 bound to nsp14-ExoN domain reveals an exoribonuclease with both structural and functional integrity

Yang, J, Chen, Z, Sun, H, Yang, F, Zheng, Y, Ye, F, Deng, D, Xiao, Q, Cao, Y, Wang, L, Wen, A, Chen, H, Lin, X, Lu, G, Lin, S, Dong, H

Nucleic Acids Res 2021
33083157 Mutations of SARS-CoV-2 nsp14 exhibit strong association with increased genome-wide mutation load

Suner, A, Oktay, Y, Eskier, D, Karakülah, G

PeerJ 2020
  Genomic diversity of SARS-CoV-2 can be accelerated by a mutation in the nsp14 gene

Takada, K, Nakagawa, S, Watanabe, T, Ueda, MT

   
34942146 Activation of the SARS-CoV-2 NSP14 3'-5' exoribonuclease by NSP10 and response to antiviral inhibitors

Copeland, WC, Riccio, AA, Sullivan, ED

J Biol Chem 2022
33705595 New targets for drug design: importance of nsp14/nsp10 complex formation for the 3'-5' exoribonucleolytic activity on SARS-CoV-2

Saramago, M, Arraiano, CM, Matos, RG, Viegas, SC, Souza, CS, Costa, VG, Bárria, C, Lousa, D, Domingues, S, Soares, CM

FEBS J 2021
33933612 Reconstitution and functional characterization of SARS-CoV-2 proofreading complex

Ma, Z, Pourfarjam, Y, Kim, IK

Protein Expr Purif 2021
32938769 The Enzymatic Activity of the nsp14 Exoribonuclease Is Critical for Replication of MERS-CoV and SARS-CoV-2

Bredenbeek, PJ, Posthuma, CC, Zevenhoven-Dobbe, JC, Ogando, NS, Snijder, EJ, van der Meer, Y

J Virol 2020
34315827 Structural basis of mismatch recognition by a SARS-CoV-2 proofreading enzyme

Schatz, DG, Becker, ST, Shi, W, Yang, Y, Liu, B, Liu, C

Science 2021
33821277 Structure and dynamics of SARS-CoV-2 proofreading exoribonuclease ExoN

Amaro, RE, Shi, K, Yin, L, Durfee, C, Banerjee, S, Belica, C, Moeller, NH, Aihara, H, Demir, Ö

bioRxiv 2021
Participants
Input
Output
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Catalyst Activity

3'-5'-exoribonuclease activity of SARS coronavirus gRNA:RTC:nascent RNA minus strand with mismatched nucleotide [double membrane vesicle viral factory outer membrane]

Physical Entity
SARS coronavirus gRNA:RTC:nascent RNA minus strand with mismatched nucleotide [double membrane vesicle viral factory outer membrane] (Severe acute respiratory syndrome coronavirus 2)
Activity
3'-5'-exoribonuclease activity (GO:0000175)
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)
Reviewed
Acencio, ML  (2020-09-09)
Created
Cook, J  (2020-07-07)
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