The mode of transcription is similar to eukaryotic transcriptional events in which the process is divided into three steps: (1) the initiation step, when a transcription initiation complex is assembled at the promoter region located upstream of the transcriptional start site, allowing for the recruitment of the RNA polymerase, (2) the elongation step, in which, the polymerase is recruited to template DNA, is activated by phosphorylation of the carboxy-terminal domain (CTD), and proceeds to transcribe the template DNA to RNA, and (3) the termination step, which involves the recognition of specific signals, including the polyadenylation signal. Recent discoveries indicate that 2-O-methylation of cap structures is recognized by innate immune interferons to differentiate host versus virus transcripts. Many viruses that replicate in the cytoplasm compartmentalize their genome replication and transcription in organelle-like structures that enhance replication efficiency and protection from host defenses. Abstract. This type of genome template for replication/transcription is observed in all dsDNA viruses that replicate in the nucleus or in the cytoplasm. This motivated new research, in which we searched for RNA viruses circulating in UK bats. The four main types of polymerases used by viruses depend on their genomic constitution and site of replication, that is, nucleus or cytoplasm, and include: RNA-dependent RNA polymerases (RdRps), RNA-dependent DNA polymerases, DNA-dependent RNA polymerases, and DNA-dependent RNA polymerases. Whereas DNA viruses need only to generate mRNA, these RNA viruses without a DNA stage have to synthesize both viral RNA and mRNA. Author Summary RNA-dependent RNA polymerase (RdRp) is an enzyme that catalyzes the replication from an RNA template and is encoded in the genomes of all RNA viruses. Retroviruses have different target sites of integration; for example, lentivirus DNA insertion occurs preferentially in active transcription units (TUs), whereas Murine leukemia virus integrates at or close to promoter regions located at the 5 terminus of CpG and TUs islands. Reverse transcriptase , a viral enzyme that comes from the virus itself, converts the viral RNA into a complementary strand of DNA, which is copied to produce a double stranded . Of note, two genome subgroups can be distinguished in this group: nonsegmented and segmented. Inhibition of cellular mRNA export out of the nucleus by targeted disruption of the structure of the NPC. Another capping mechanism used by negative-sense RNA viruses (e.g., influenza viruses) is that of cap snatching from nascent host pre-mRNAs (see later). Linear ssDNA adeno-associated viruses (AAVs) are an example. In particular, recent studies with diverse positive-strand RNA viruses have further elucidated the ultrastructure of membrane-bound RNA . Alternative splicing is regulated by cellular and viral proteins that modulate the activity of the splicing factors U1 and U2, both of which are components of the spliceosome. As a result, viruses have evolved a number of mechanisms to allow translation to be customized to their specific needs. Transcription termination involves secondary structure mechanisms or in eukaryotic cells, RNA signals direct polyadenylation and termination. 3.2 ). However, it is becoming clear that viral RNA can persist after clinical recovery and elimination of . The processed 5 end is important because the 5 cap is the site for the assembly of the translation initiation complex, and it protects and stabilizes the mRNA strand from 5-3 exonucleolytic degradation when it is exported out the nucleus and into the cytoplasm for translation. Hoeben R.C., Uil T.G. RNA viruses,. It should be noted that in all these examples, the balance between the processes of transcription and genome replication must be properly maintained to allow efficient viral proliferation. Initiation of transcription requires the recruitment and assembly of a large multiprotein DNA-binding transcription initiation complex. The virus codes for its own RdRp, which converts the () stranded RNA into (+) RNA template strands. Translation of this mRNA generates proteins required for replication and viral encapsidation. As such, a restricted pool of dNTPs will not provide an ideal environment for viral replication. Straightforward exploitation of the cellular capping machinery is typical of DNA viruses that replicate in the nucleus. 3.3 The diversity in mechanisms used by polymerases to replicate and/or transcribe viral genomes is summarized in the following section. From the perspective of the virus, the purpose of viral replication is to allow production and survival of its kind. The strategies are reviewed in the section that follows. Viruses: PV, Poliovirus; HRV, Human rhinovirus; HHV, Human herpesvirus; TMEV, Theilers murine encephalomyelitis virus. Other strategies used by viruses include internal initiation of translation of uncapped RNAs in picornaviruses and their relatives, snatching of capped oligonucleotides from host pre-mRNAs to initiate viral transcription in segmented negative-strand RNA viruses, and recruitment of genes for the conventional, eukaryotic-type capping enzymes that apparently occurred independently in diverse groups of viruses (flaviviruses, reoviridae, poxviruses, asfarviruses, some iridoviruses, phycodnaviruses, mimiviruses, baculoviruses, nudiviruses). RNA viruses usually use the RNA core as a template for synthesis of viral genomic RNA and mRNA. RNA viruses, on the other hand, that mostly replicate in the cytoplasm, do not have access to these host mechanisms and consequently produce monocistronic sgRNAs (e.g., coronaviruses and closteroviruses), use segmented genomes where most segments are monocistronic (e.g., reoviruses and orthomyxoviruses) or translate their polycistronic mRNA into a single large protein (polyprotein) that is subsequently proteolytically cleaved (by viral or host enzymes) into functional individual proteins (e.g., picornaviruses and flaviviruses). Some of these newly synthesized viral proteins are used as the protein capsid around newly replicated viral DNA molecules. The other class of (+) RNA viruses is the retroviruses. For instance, flaviviruses (e.g., Dengue virus, West Nile virus) have a capped RNA genome that contains conserved sequences at the 5 and 3 ends, allowing for circularization and efficient translation. Strategies for Virion Formation Like bacteriophages, some animal viruses use DNA while others use RNA molecules to carry their genetic information. In some retroviruses, nuclear localization signals facilitate migration to the nucleus. This is because of the proofreading ability of the polymerase. The host cell must provide the energy and synthetic machinery and the low- molecular-weight precursors for the synthesis of viral proteins and nucleic acids. As indicated earlier, some viruses encode and/or carry the enzymatic repertoire required for genome replication and/or transcription, while others recruit host polymerases. This occurs because the initiation codon can be part of a weak Kozak consensus sequence. The step-wise assembly of replication initiation complexes at these ori sites then occurs followed by recruitment of topoisomerases that unwind dsDNA at each ori, and prevents supercoiling and torsional stress of the partially unwound template DNA. Viruses that replicate via RNA intermediates need an RNA-dependent RNA-polymerase to replicate their RNA, but animal cells do not seem to possess a suitable enzyme. Cyclins are a diverse family of proteins whose structure includes a conserved region known as the cyclin box, which is necessary for Cdk binding and activation. Other examples that follow the same strategy include rotaviruses, barley yellow dwarf viruses, and possibly Hepacivirus C (HCV). The site is secure. Cellular mRNA transcripts undergo polyadenylation through cleavage at the signal sequence AAUAAA by the CPSF (cleavage and polyadenylation specificity factor) and CSTF (cleavage stimulation factor). Both virus genome transcription and mRNA synthesis occur in three stages. This switch is widely observed in picornaviruses since their viral mRNA transcripts do not contain the m7G cap at their 5 ends. Both (+) and () ssRNA viruses replicate and transcribe their genomes using RdRp enzymes (Fig. The LTR sequences at the 3 and 5 ends of the linear viral DNA are joined to the hosts DNA in two steps called end-processing and end-joining. A replication fork or bubble is produced. Regardless of their genetic constitution, viral genomes are replicated, expressed, and assembled in association with living host cells. It is, therefore, referred to as cap-dependent discontinuous scanning. During initiation, the polymerase machinery is recruited to the viral promoter and synthesis begins at or near the 3 end of the template. Discontinuous DNA synthesis on the displaced strand template produces linear dsDNA containing multiple copies of the genome. These entities do not undergo division, but rather generate new particles through the assembly of preformed components. By contrast, most RNA viruses cause acute infections that are cleared from the host as they lack the mechanisms to persist. Orthomyxoviridae to polyadenylate their mRNAs. This involves template switching of the RNA polymerase and the production of chimeric RNAs consisting of a 5 common leader sequence derived from the 5 terminus of the genomic RNA fused to the body of the transcript (i.e., the 3 terminal end). Furthermore, while the great majority of cellular mRNAs are monocistronic, viruses must often express multiple proteins from their mRNAs. Inclusion in an NLM database does not imply endorsement of, or agreement with, Virus particles, often termed virions are assembled through two strategies. Dubois J., Terrier O., Rosa-Calatrava M. Influenza viruses and RNA splicing: doing more with less. Ribosomal shunting occurs when the ribosomal initiation complex is loaded onto an mRNA at the 5-cap but the process of scanning for the start codon progresses for only a short distance, bypasses a large internal leader region, and initiates translation at another start codon located downstream of the leader sequence (Fig. A DNA virus won't have an RNA polymerase gene to mediate transcription, so it has to be in the nucleus - where the host RNA polymerase is. Picornaviruses are able to suppress cellular RNA decay factors, and polioviruses and human rhinoviruses produce viral proteases that degrade Xrn1, Dcp1, Dcp2, Pan3 (a deadenylase), and AUF1decay factors. The mechanism of ribosome shunting has not been described in molecular detail. DNA viruses are more stable than RNA viruses, therefore less prone to mutations, and they replicate in the nucleus of their host's cells instead of the cytoplasm. On their own, viruses lack the complete machinery necessary for many life-sustaining functions. Ribosomal shunting. Nature's stern discipline enjoins mutual help at least as often as warfare. As such, in order for HCV to create replication compartments and increase sites of assembly, the RNA virus requires both the synthesis of fatty acids, for example, cholesterol, sphingolipids, phosphatidylcholine, and phosphatidylethanolamine, and formation of lipid droplets. Replication involves two phases; transcription of the pgRNA from virus DNA in the nucleus followed by reverse transcription in the cytoplasm. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. 3.14 The spliceosome is made up of the snRNAs (small nuclear RNAs) U1, U2, U4, U5, and U6, together with various regulatory factors. ssDNA-binding proteins keep the single strands of DNA separate. government site. https://doi.org/10.1007/s00709-011-0327-9. Viral proteins often consist of multiple domains or are produced as polyprotein precursors, which must be processed before they can be functional. The high rate of mutation in RNA viruses may mean an increased dependency on chaperones for the gene products of these viruses. Replication of HCV occurs on specific lipid raft domains, whereas assembly occurs in lipid droplets. RNA viruses, particularly positive-strand RNA viruses, interact with the nucleolus to usurp host-cell functions and recruit nucleolar proteins to facilitate virus replication. Alternative and more efficient mechanisms of expressing multiple proteins from a single viral mRNA involve internal ribosome entry, leaky scanning, ribosome shunting, reinitiation, ribosomal frameshifting, and stop codon read-through. This is the classical mode of replication used by eukaryotes and most nuclear dsDNA viruses, including the majority of phages. Initiation of translation of cellular mRNA occurs through the recruitment and assembly of a multisubunit translation initiation complex at the 5 end of the mRNA strand (Fig. 2A oligopeptides interact with the ribosomal exit tunnel to initiate a stop codon-independent termination of translation at the final proline codon of 2A. As alluded to in the previous sections, many viral transcripts have marked structural differences from cellular mRNAs that preclude translation initiation, such as the absence of a 5 cap structure or the presence of highly structured 5 untranslatable leader regions containing replication and/or packaging signals. Addition of the 3 poly(A) tail is another end-processing mechanism required to protect the mRNA transcript from nucleolytic degradation in the cytoplasm and enable mRNA stability. In this way, the viral dsRNA does not enter the cytoplasm and evades the hosts immune system. ). ). Stuttering mechanism. In nonsegmented negative RNA viruses, obligatory sequential transcription dictates that termination of each upstream gene is required for initiation of downstream genes. glycosylation); (3) nucleic acid synthesis, for although some viruses code for an enzyme or enzymes involved in the synthesis of their nucleic acids, they do not usually contribute all the polypeptides involved and are reliant on various host factors; and (4) structural components of the cell, in particular lipid membranes, involved in virus replication. Some cellular chaperones, for example, Hsp70, are used to accelerate the maturation of viral proteins and are involved in regulating the viral biological cycle. 1The University of the West Indies, St. Augustine, Trinidad and Tobago, 2The University of the West Indies, Mona, Jamaica. As will be seen, the mechanisms are dictated by the nature and structure of the viral genomes. For other RNA and DNA viruses, viral mRNA is synthesized upon entry into the host cell. Cap snatching of cellular mRNA. 3.13 Other viruses utilize mechanisms that result in G2/M arrest through either inactivation of Cdk1 at the G2/M checkpoint and/or at the interference with mitotic progression. Many ssRNA(+) viruses lack a poly(A) tail, but are still efficiently translated. Some termination codons are referred to as leaky depending on the nature of the base positioned after the stop codon (e.g., UGAC) where they allow read through at frequencies ranging from 0.3% to 5%.
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why do rna viruses replicate in the cytoplasm
