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Open AccessArticle

Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication

1
Inst. of Biochemistry, Medical Faculty, Justus-Liebig-University, 35392 Giessen, Germany
2
Inst. of Virology, Faculty of Veterinary Medicine, Justus-Liebig-University, 35392 Giessen, Germany
3
Genevention GmbH, 37079 Göttingen, Germany
4
RNA Bioinformatics and High Throughput Analysis, Faculty of Mathematics and Computer Science, Friedrich Schiller University Jena, 07743 Jena, Germany
5
Lomonosov Moscow State University, Belozersky Inst. of Physico-Chemical Biology, Moscow 119234, Russia
6
Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry, Moscow 117997, Russia
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Int. J. Mol. Sci. 2020, 21(18), 6955; https://doi.org/10.3390/ijms21186955
Received: 22 July 2020 / Revised: 26 August 2020 / Accepted: 15 September 2020 / Published: 22 September 2020
Hepatitis C virus (HCV) infects liver cells and often causes chronic infection, also leading to liver cirrhosis and cancer. In the cytoplasm, the viral structural and non-structural (NS) proteins are directly translated from the plus strand HCV RNA genome. The viral proteins NS3 to NS5B proteins constitute the replication complex that is required for RNA genome replication via a minus strand antigenome. The most C-terminal protein in the genome is the NS5B replicase, which needs to initiate antigenome RNA synthesis at the very 3′-end of the plus strand. Using ribosome profiling of cells replicating full-length infectious HCV genomes, we uncovered that ribosomes accumulate at the HCV stop codon and about 30 nucleotides upstream of it. This pausing is due to the presence of conserved rare, inefficient Wobble codons upstream of the termination site. Synonymous substitution of these inefficient codons to efficient codons has negative consequences for viral RNA replication but not for viral protein synthesis. This pausing may allow the enzymatically active replicase core to find its genuine RNA template in cis, while the protein is still held in place by being stuck with its C-terminus in the exit tunnel of the paused ribosome. View Full-Text
Keywords: HCV; translation; ribosome pausing; rare codon; Wobble codon; replication; minus strand; negative-strand; antigenome HCV; translation; ribosome pausing; rare codon; Wobble codon; replication; minus strand; negative-strand; antigenome
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MDPI and ACS Style

Gerresheim, G.K.; Hess, C.S.; Shalamova, L.A.; Fricke, M.; Marz, M.; Andreev, D.E.; Shatsky, I.N.; Niepmann, M. Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication. Int. J. Mol. Sci. 2020, 21, 6955. https://doi.org/10.3390/ijms21186955

AMA Style

Gerresheim GK, Hess CS, Shalamova LA, Fricke M, Marz M, Andreev DE, Shatsky IN, Niepmann M. Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication. International Journal of Molecular Sciences. 2020; 21(18):6955. https://doi.org/10.3390/ijms21186955

Chicago/Turabian Style

Gerresheim, Gesche K.; Hess, Carolin S.; Shalamova, Lyudmila A.; Fricke, Markus; Marz, Manja; Andreev, Dmitri E.; Shatsky, Ivan N.; Niepmann, Michael. 2020. "Ribosome Pausing at Inefficient Codons at the End of the Replicase Coding Region Is Important for Hepatitis C Virus Genome Replication" Int. J. Mol. Sci. 21, no. 18: 6955. https://doi.org/10.3390/ijms21186955

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