As DNA viruses exploit the host cell machinery to complete their life cycles they carrysmall genomes encoding mostly viral structural proteins, like those for the capsid. "A copy machine that causes the delivered RNA to replicate in the body; these so-called replicons, or copied RNA, ensure powerful responses with few side effects after immunization with a single . This blog shares information and resources about pathogenic bacteria, viruses, fungi, and parasites. There are two kinds of mRNA editing: (1) cotranscriptional editing through polymerase slippage and (2) posttranscriptional editing. Several viruses can inhibit nuclear export of cellular mRNAs by disrupting nuclear export receptors (exportin1 and TIP-associated protein) and nucleoporins that comprise the NPC to compromise their function in nucleocytoplasmic trafficking of cellular mRNA. Of note, two genome subgroups can be distinguished in this group: nonsegmented and segmented. The process of replication is typically divided into the phases of attachment, entry, uncoating, genome replication and expression, assembly, maturation, and finally, egress or release from the host cell. https://doi.org/10.1046/j.1365-2613.2001.00165.x. Once inside the nucleus and after association with host chromosomes, viral IN catalyzes insertion of viral sequences into the host DNA (Fig. Alternative splicing. . 8600 Rockville Pike The CTD of host RNA polymerase contains 52 heptapeptide repeats (YSPTSPS) and is phosphorylated primarily at serine amino acids multiple times during the transcription process (Fig. Sequence complementarity shared between the nucleotides within the cleavage site of the donor mRNA and the viral RNA facilitates successful cap snatching. 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). 3.7 Typically, these macromolecules are recruited and concentrated into specific cytoplasmic or nuclear compartments. As a library, NLM provides access to scientific literature. This occurs because the initiation codon can be part of a weak Kozak consensus sequence. As such, many dsRNA viruses undergo replication within their icosahedral capsids. Discontinuous DNA synthesis on the displaced strand template produces linear dsDNA containing multiple copies of the genome. Hsp70 can refold denatured proteins, which negates some of the destabilizing alterations in structural proteins as a result of mutated genes. Termination leads to the release of the newly synthesized RNA strand and the dissociation of the polymerase from the template. Viruses that do not replicate in the nucleus and do not have access to host polymerases, typically encode their own polymerases for replication. Once inside a cell, the enzymes transcribe one of the RNA strands of the dsRNA genome to ssRNA(+) within the virion, which upon release into the cytoplasm (through channels in the virion) is translated by the host cell machinery. DNA viruses experience low mutation rates. In addition, these ssRNA(+) can act as a template for () RNA strand synthesis that is converted back into a dsRNA genome for packaging. The pathways leading from genome to message vary among different viruses (Fig. Mutations may be neutral or silent (because of genetic code redundancy) and those that interfere with viral replicative mechanisms are eliminated from the viral population. During initiation, the polymerase machinery is recruited to the viral promoter and synthesis begins at or near the 3 end of the template. The LTRs of linear viral DNA are joined to the hosts DNA in two steps called end-processing and end-joining. Many ssRNA(+) viruses lack a poly(A) tail, but are still efficiently translated. Ribosomal frameshifting. Most ssRNA(+) viruses (e.g., flaviviruses and nidoviruses) encode their own capping enzymes and some unsegmented ssRNA() viruses (including Rabies virus (Rabies lyssavirus), measles virus (Paramyxoviridae), and Ebola virus (Filoviridae)) are capped by their polymerase. Most viruses produce an endonuclease that cleaves host mRNAs, which are then degraded by host exonucleases (e.g., Xrn1 in mammals). Replication involves two phases; transcription of the pgRNA from virus DNA in the nucleus followed by reverse transcription in the cytoplasm. DNA viruses replicate their genomes using DNA polymerase enzymes and transcribe their mRNA using DNA-dependent RNA polymerase enzymes. [2] The 3 end may be either naked or polyadenylated. Replication of HCV occurs on specific lipid raft domains, whereas assembly occurs in lipid droplets. This is an enzyme that converts one . It has been proposed that such viruses can induce quiescent cells to enter the cell cycle, specifically the S phase, in order to create an environment that generates factors, such as nucleotides, that are required for viral replication. 1 ribosomal frameshift, common to parvoviruses, changes the amino acids encoded in the mRNA strand by moving the reading frame 1-base down (1). Moon S.L., Wilusz J. Cytoplasmic viruses: rage against the (cellular RNA decay) machine. On their own, viruses lack the complete machinery necessary for many life-sustaining functions. A common strategy for host RNA degradation by divergent viruses. 3.9 As indicated earlier, some viruses encode and/or carry the enzymatic repertoire required for genome replication and/or transcription, while others recruit host polymerases. The cap-stealing mechanisms used by segmented RNA viruses to generate their mRNAs circumvent this innate detection system. DNA viruses, as might be expected, mostly replicate in the nucleus where host cell DNA is replicated and the biochemical apparatus necessary for this process is located. Viral proteins often consist of multiple domains or are produced as polyprotein precursors, which must be processed before they can be functional. Therefore, this type of animal RNA virus needs to code for an RNA-dependent RNA polymerase. Upon recognition of the polyadenylation signal, RdRp moves back and forth over this stretch of U residues, reiteratively copies these residues, and produces a stretch of adenines effectively, a poly(A) tail at the 3 end of the viral mRNA. In these viruses, the RNA polymerase reads the same template base more than once, creating insertions or deletions in the mRNA sequence, thereby generating different mRNAs that encode different proteins. Cripavirus IRES also allows translation initiation on an alanine or glutamine tRNA and not necessarily the methionine tRNA. The parental virus (virion) gives rise to numerous progeny, usually genetically and structurally identical to the parent virus. Elongation and termination of transcription are coupled to end-processing of the mRNA where the 5 cap (added co- or posttranscriptionally) and 3 poly(A) tail are generated on the ends of the mRNA strand. As a result, viruses and their hosts have been involved in a long-standing battle of adaptation and counter-adaptation for gene expression and nucleic acid synthesis. Poly(A) tails, at the 3 end, are associated with poly(A)-binding proteins that stabilize the mRNA in the cytoplasm by protecting the 3 end of the newly synthesized mRNA against exoribonucleolytic degradation. 3.4 Replication Life cycle of Japanese encephalitis virus a +ssRNA virus: attachment, endocytosis, membrane fusion, uncoating, translation, RNA replication, assembly, maturation, and release. Stop codons are recognized by release factors (eRF1 and eRF3), which promote hydrolysis of the peptidyl-tRNA bond in the peptidyl transferase center (P-site) of the large ribosomal subunit. 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. ). RNA viruses, particularly positive-strand RNA viruses, interact with the nucleolus to usurp host-cell functions and recruit nucleolar proteins to facilitate virus replication. Retroviruses and other RNA viruses also interfere with the host cell cycle. In addition, the physiological state of the infected cell dictates whether host mRNA transcripts undergo cap-dependent translation or cap-independent translation. ssDNA-binding proteins keep the single strands of DNA separate. De novo initiation is used by RNA viruses, including those with genomes of positive, negative, ambisense, and dsRNA. This mechanism pertains to all members of the family Retroviridae. The coat protein or capsid is a meta-stable structure that must be specifically assembled in a preordered arrangement without reaching minimum free energy; yet must be disassembled upon entry of the host cell. Rep creates a nick between the hairpin and coding sequences. DNA viruses need only to generate mRNA and thus replication involves strategies that are familiar in cell biology: transcription of mRNA from dsDNA and replication of dsDNA within the cell nucleus. Not all mutations generated will persist in a virus population, however. Once viral genome replication factors and the template are assembled into a complex, the polymerase synthesizes a new complementary strand, without dissociation from the template, and by the repeated addition of a nucleoside monophosphate to the 3 end of the growing RNA strand. AAVs encode the Rep78 protein that contains amino acid sequence motifs similar to RCR initiator proteins. These entities do not undergo division, but rather generate new particles through the assembly of preformed components. Viruses can engage in targeted disruption of cellular mRNA export pathways to promote preferential viral gene expression (Fig. The virus genome integrates into the host genome and can be passed from parent to offspring should integration occur in germline cells. Yarbrough M.L., Mata M.A., Sakthivel R., Fontoura B.M.A. Some viruses (herpesviruses, bunyaviruses) counteract this phosphorylation at serine amino acids to inactivate RNA polymerase, while other viruses (orthomyxviruses, togaviruses) disrupt cellular RNA polymerase function by signaling ubiquitination of the enzyme and its subsequent degradation by proteasomal action. For productive infection, viruses must then utilize this machinery, and remain both stable and undetected in the cell. RT is virus-encoded as the host cell does not require this enzyme for its nuclear metabolism. https://doi.org/10.1371/journal.ppat.1003762. DNA viruses often persist in the body of their host, becoming latent and recurring many months or years later. 3.5 Viral genomes carry out multiple functions serving as mRNAs for translation in some instances and/or templates for genome transcription and replication. The third mechanism uses discontinuous RNA synthesis while making the minus-strand RNA templates. One of the key features of viruses is their reliance on living cells for replication and propagation. The TATA box-binding protein (TBP) is inhibited by HPV-16 E7 protein or by adenovirus E1A protein, and it is cleaved by the poliovirus 3C protease; Thogoto virus ML protein interacts with host TFIIB and strongly inhibits IRF3 and NF-kappa-beta-regulated promoters; HHV-3 IE63 targets TFIIE, while Rift Valley fever phlebovirus (RVFV) targets TFIIH complex. Viruses that replicate in the nucleus must out-compete cellular mRNAs to export viral mRNAs out of the nucleus for translation into virus gene products in the cytoplasm. Regardless of their genetic constitution, viral genomes are replicated, expressed, and assembled in association with living host cells. ). Hoeben R.C., Uil T.G. Both pathways require enzymatic activities that are not usually found in uninfected host cells and as a result, these viruses code for the requisite enzymes, which are either expressed early in infection or they are copackaged with the viral genome during the assembly of virions in preparation for the next round of infection. Replication, therefore, occurs in membrane-associated replication factories in an effort to avoid the hosts immune defense response. Cavallari I., Rende F., DAgostino D.M., Ciminale V. Converging strategies in expression of human complex retroviruses. Different strategies used by viruses to down regulate host transcription. Viral genomes provide examples of almost every structural variation imaginable. ssRNA(+) molecules serve as templates for replication and transcription. Small DNA viruses, for example, Papillomaviridae, Polyomaviridae, and Parvoviridae, do not encode the entire repertoire of proteins required for viral replication because of their limited genome size. Strategies for Virion Formation Like bacteriophages, some animal viruses use DNA while others use RNA molecules to carry their genetic information. Coronaviruses use an unusually large collection of RNA-synthesizing and RNA-processing enzymes to express and replicate a genome that is two to three times larger than that of most other RNA viruses. The resulting transcripts carrying information encoding viral proteins are then transported to the cytoplasm and seen as a template by the host cell ribosomes. Depending on the virus, sgRNAs may be generated during internal initiation on a minus-strand RNA template and require an internal promoter or there is the generation of a prematurely terminated minus-strand RNA that is used as template to make the sgRNAs. The rate by which mutations occur is universally determined as the number of nucleotide substitutions per base per generation. RdRp then uses the negative sense genome as a template to synthesize a positive-sense antigenome. Shutoff of host translation machinery by viral interference with specific eukaryotic translation initiation factors and poly(A) binding protein (PABP). 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. professor, I am teaching microbiology and immunology to medical and nursing students at PAHS, Nepal. The copying of RNA into DNA is carried out by viral enzyme reverse transcriptase and occurs in cytoplasm. When the cell exhibits normal housekeeping functions, translation of cellular mRNAs is carried out by a cap-dependent mechanism; however, under stressful conditions, such as heat shock, viral infection, hypoxia, and irradiation, the translation mechanism switches from cap dependency to IRES-driven mechanisms. A replication fork or bubble is produced. DNA replication begins at a specific site in the viral genome, called origin of replication, or ori. Some viruses (e.g., Human alphaherpesvirus 1) have multiple ori sites. Cellular lipid metabolism is affected at three levels: enhanced lipogenesis, impaired degradation, and disruption of export, which is subsequently manifested in the host as HCV-associated pathogenesis. These viruses contain secondary structures at the ends of their DNA called inverted terminal repeats (ITRs). Coronaviruses (CoVs) are the largest group of viruses belonging to the Nidovirales order, which includes Coronaviridae, Arteriviridae, Mesoniviridae, and Roniviridae families. The newly synthesized () RNA is later encapsidated. Stuttering mechanism. On the other hand, () RNA, which is not mRNA, requires a virus-encoded RNA-replicating enzyme that is carried within the virion, to copy () RNA to monocistronic (+) RNA that is recognized by the host cell translation machinery. Here, multiple cycles of continuous copying of a circular template, followed by discontinuous DNA synthesis on the displaced strand template produces linear dsDNA molecules containing multiple copies of the genome (concatemers). Dotted lines indicate alternative splice sites. Primer-dependent initiation requires either an oligonucleotide primer or a protein primer, to provide the initial 3-hydroxyl for addition of the first incoming nucleotide. Depending upon the retrovirus, preintegration complexes either enter the nuclei of nondividing cells through the nuclear pore complex (NPC) (e.g., HIV) or enter when the nuclear membrane dissolves during cell division [e.g. Single-stranded RNA genomes, however, exist in two forms: either the sense or the plus (+) strand or the nonsense or minus () strand. Other viruses arrest RNA Pol activity by signaling ubiquitination of the transcribing enzyme, which is subsequently degraded by the proteasome. The ssRNA(+) can serve as the template for translation and does not undergo any modification prior to translation. An official website of the United States government. 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). Covalently closed virus dsDNA serves as a template for host polymerase transcription and the generation of viral pgRNA. After initiation of viral mRNA transcription, DNA viruses and some dsRNA viruses (e.g., reoviruses) acquire a 5-terminal cap structure (m7Gppp[5]N-; where N is the first nucleotides of the nascent RNA) using host enzymes. Some of these newly synthesized viral proteins are used as the protein capsid around newly replicated viral DNA molecules. The ssRNA(+) strand is translated after viral entry into the host cell. In this way, the viral dsRNA does not enter the cytoplasm and evades the hosts immune system. Pararetroviruses (e.g., members of Caulimoviridae) are circular, dsDNA viruses that transition through an RNA intermediate (pregenomic RNA or pgRNA) in a manner that is reminiscent of retrovirus replication. Transcription can be viewed as a highly regulated 3-phase process: initiation, elongation, and termination. the contents by NLM or the National Institutes of Health. The DNA polymerase involved must exhibit a high level of processivity and strand displacement characteristics. T-even phage is a good example of a well-characterized class of virulent phages. Production of viral proteins often requires noncanonical decoding events (or recoding) on certain codons during translation due to the restricted coding capacity of a small genome size. Bethesda, MD 20894, Web Policies Cellular splicing machinery typically generates mature viral mRNAs. 3.13 DdDp, DNA-dependent DNA polymerase; DdRp, DNA-dependent RNA polymerase; RdRP, RNA- dependent RNA polymerase; RT, reverse transcriptase. 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.
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