SARS-CoV-2 News: Cambridge Led Study Reveals That SARS-CoV-2 Utilizes Unique “Genetic Origami” To Enter and Multiply Inside Human Host Cells
: Researchers from the University of Cambridge, in collaboration with Justus-Liebig University, Germany, have uncovered how the genome of SARS-CoV-2 ie the coronavirus that causes COVID-19 utilizes ‘genome origami’ to infect and replicate successfully inside host cells.
Discovery of shape of the SARS-CoV-2
genome after infection could
inform the development of effective drugs that target specific parts of the virus genome, in the fight against COVID-19.
is a family of positive-strand RNA viruses that includes SARS-CoV-2, the etiologic agent of the COVID-19 pandemic. Bearing the largest single-stranded RNA genomes in nature, coronaviruses are critically dependent on long-distance RNA-RNA interactions to regulate the viral transcription and replication pathways.
The study team experimentally mapped the in vivo
RNA-RNA interactome of the full-length SARS-CoV-2 genome and subgenomic mRNAs. They uncovered a network of RNA-RNA interactions spanning tens of thousands of nucleotides. These interactions reveal that the viral genome and subgenomes adopt alternative topologies inside cells, and engage in different interactions with host RNAs.
Notably, the study team discovered a long-range RNA-RNA interaction - the FSE-arch - that encircles the programmed ribosomal frameshifting element. The FSE-arch is conserved in the related MERS-CoV and is under purifying selection. The study findings illuminate RNA structure based mechanisms governing replication, discontinuous transcription, and translation of coronaviruses, and will aid future efforts to develop antiviral strategies.
The study findings were published in the peer reviewed journal: Molecular Cell
The SARS-CoV-2 is one of many coronaviruses. All share the characteristic of having the largest single-stranded RNA
genome in nature. This genome contains all the genetic code the virus needs to produce proteins, evade the immune system, and replicate inside the human body. Much of that information is contained in the 3D structure adopted by this RNA genome when it infects cells.
The study team says most current work to find drugs and vaccines for COVID-19 is focused on targeting the proteins of the virus. Because the shape of the RNA molecule is critical to its function, targeting the RNA directly with drugs to disrupt its structure would block the lifecycle and stop the virus replicating.
The study team uncovered the entire structure of the SARS-CoV-2 genome inside the host cell, revealing a network of RNA-RNA interactions spanning very long sections of the genome. Different functional parts along the genome need to work together despite the great distance between them, and the new structural data shows how this is accomplished to enable the coronavirus life cycle and cause disease.
Dr Omer Ziv from the University of Cambridge’s Wellcome Trust/Cancer Research UK Gurdon Institute told Thailand Medical News, “The RNA genome of coronaviruses is about three times bigger than an average viral RNA genome, it is huge.”
Dr Ziv added, “Researchers previously proposed that long-distance interactions along coronavirus genomes are critical for their replication and for producing the viral proteins, but until recently we didn’t have the right tools to map these interactions in full. Now that we understand this network of connectivity, we can start designing ways to target it effectively with therapeutics.”
It is known that in all cells the genome holds the code for the production of specific proteins, which are made when a molecular machine called a ribosome runs along the RNA reading the code until a ‘stop sign’ tells it to terminate. In coronaviruses, there is a special spot where the ribosome only stops 50% of the times in front of the stop sign. In the other 50% of cases, a unique RNA shape makes the ribosome jump over the stop sign and produce additional viral proteins. By mapping this RNA structure and the long-range interactions involved, the new research uncovers the strategies by which coronaviruses produce their proteins to manipulate our cells.
Dr Lyudmila Shalamova, a co-lead investigator at Justus-Liebig University, Germany added, “We show that interactions occur between sections of the SARS-CoV-2 RNA that are very long distances apart, and we can monitor these interactions as they occur during early SARS-CoV-2 replication.”
Co-lead of this study Dr Jon Price, a postdoctoral associate at the Gurdon Institute has developed a free, open-access interactive website hosting the entire RNA structure of SARS-CoV-2. This will enable researchers world-wide to use the new data in the development of drugs to target specific regions of the virus’s RNA genome.
The genome of most human viruses is made of RNA rather than DNA
. Dr Ziv developed methods to investigate such long-range interactions across viral RNA genomes inside the host cells, in work to understand the Zika virus genome. This has proved a valuable methodological basis for understanding SARS-CoV-2.
The study team additionally discovered long-distance interactions unique to the sgmRNA (subgenomic mRNAs) Previous models of the SARS-CoV-2 and related viruses mainly analyzed structural population averages, i.e. assuming that all copies of the genome and sgmRNA have a single static conformation. Yet, the complex life cycle of viral RNA genomes, i.e. their engagement with multiple cellular and viral machineries such as the ones for replication, transcription, and translation, suggests a dynamic RNA structure, as this study and others have reported for Zika virus and for HIV-1.
This study’s structural analysis of SARS-CoV-2 reveals a high level of structural dynamics whereby alternative high-order conformations, some of which involve long-distance base-pairing, co-exist in vivo. For example, nucleotides 5,660-5,680 in ORF1a interact with three alternative distal regions: 3.6 kb upstream, 3.4 kb downstream, and 2 kb upstream (Figure 3, arches 4, 5 and 8 respectively), and the 5′ UTR interacts with ORF1a as well as with the 3′ UTR. In contrast, the team finds that ORF N sgmRNA is held in a single dominant conformation where the leader sequence interacts exclusively with a region 0.8 kb downstream.
In summary, the team discovers the co-existence of alternative SARSCoV-2 gRNA and sgmRNA topologies, held by long-range base-pairing between regions tens of thousands of nucleotides apart. Each topology brings in physical proximity previously characterized and new elements involved in viral replication and discontinuous transcription, therefore offering a model for facilitating distinct patterns of template switching to produce the complete SARS-CoV-2 transcriptome.
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