Strategies Of Replication

Strategies of Replication 37

having their genctic information encoded in RNA. RNA viruses with different types of genomes (single-stranded or double-stranded, positive or negative sense, linear or segmented) have necessarily evolved different routes to the production of mRNA. In the case of ssRNA viruses of positive sense, the viral RNA itself functions as messenger, whereas all other types of viral RNA must first be transcribed to mRNA. Since eukaryotic cells contain no RNA-dependent RNA polymerase, negative sense ssRNA viruses and dsRNA viruses must carry an RNA-dependent RNA polymerase in the virion.

Further, eukaryotic cells normally produce "gene-length" mRNA molecules for direct translation into individual proteins, rather than reinitiating translation part way along a polycislronic mRNA. Nuclear DNA viruses use the cellular mechanism of cleavage (and sometimes splicing) of their poly-cistronic RNA transcripts to yield monocistronic mRNA molecules. RNA viruses, most of which replicate in the cytoplasm and hence do not have access to the RNA processing and splicing enzymes of the nucleus, have developed a remarkable diversity of solutions to the problem. Some RNA viruses have a segmented genome in which each molecule is, in general, a separate gene. Others have a polycistronic genome but produce monocistronic RNA transcripts by termination and reinitiation of transcription. Yet others make use of a nested set of overlapping RNA transcripts, each of which is translated into a single gene product. Finally, some have a polycistronic viral RNA which is translated into a polyprotein that is later cleaved proteolytically to yield the final products.

The diverse strategies followed by viruses of different families for transcription and translation are illustrated diagrammatically in Fig. 3-4 (for DNA viruses) and Fig 3-5 (for RNA viruses) and described below.

Family

Papovaviridae Adenoviridae dsDNA Herpesviridae

Genome Transcriptase RNA transcripts cellular spliced

spiced

Hepadnaviridae --

ss/dsDNA

viral reverse transcriptase

Fig. 3-4 Simplified diagram showing essential features of the transcription and translation of DNA viruses The sense of each nuclcii acid molecule is indicated by an arrow (f to the right, - to the left) l;or simplicity the number of mliNA and protein species for each virus has been arbitrarily shown as four See text for details

DNA Viruses

Papovaviruses, Adenoviruses, Herpesviruses

The papovaviruses, adenoviruses, and herpesviruses have in one respect the most straightforward strategy of replication, the viral DNA being transcribed within the nucleus by cellular DNA-dependent RNA polymerase II. There are two or more cycles of transcription, the various transcription units (groups of genes under the control of a single promoter) being transcribed in a given temporal sequence. Polycistronic but subgenomic RNA transcripts (corresponding to several genes but less than the whole genome) undergo cleavage and splicing to produce monocistronic rnRNAs, introns being removed in the process.

Poxviruses

Poxviruses, which replicate in the cytoplasm, carry their own transcriptase (DNA-dependent RNA polymerase) in the virion. The very large genomes of poxviruses encode numerous other enzymes that make them virtually independent of the cell nucleus. Monocistronic mRNAs are transcribed directly from the viral DNA.

Parvoviruses

The ssDNA ol the parvoviruses uses cellular DNA polymerase to synthesize dsDNA, which is then transcribed in the nucleus by cellular DNA-dependent RNA polymerase II and the transcripts are processed by splicing to produce mRNAs.

Hcpadnaviruses

Hepadnavirus replication is unique in that it involves reverse transcription of an RNA intermediate to replicate the DNA genome—the mirror image of the process followed by the more extensively studied retroviruses. A super-coiled form of the viral DNA is transcribed in the nucleus by cellular DNA-dependent RNA polymerase II to produce both subgenomic and full-length RNA transcripts. The former serve as mRNA; the latter, known as the pro-genome, migrates to the cytoplasm where it serves as a template for the viral reverse transcriptase, and the minus sense DNA strand produced is in turn the template for synthesis ol the dsDNA by the viral DNA polymerase.

RNA Viruses

Picomaviruses, Togaviruses, Flaviviruses, Caliciviruses

The positive sense ssRNA viruses in the families Picornavindae, Togaviridae, i'iavivindac, and Calicwiridae require no transcriptase in the virion, since the virion RNA itself functions as mRNA (see Fig. 3-5). The genome of the picor-naviruses and flaviviruses, acting as a single polycistronic mRNA, is translated directly info a single poli/protein which is subsequently cleaved to give the individual viral polypeptides. One of these proteins is an RNA-dependent RNA polymerase, which replicates the viral genome, transcribing viral RNA

Family Picomaviridae

Togaviridae Cahciviridae

Genome

Virion RNA

transcriptase transcripts

J cleaved J RNA polymerase cleaved

Coronavindae

RNA polymerase

Nested set ol

^ / RNA transcripts

ParamyxovtrkSae ^_

Rhabdoviridae (-)ssRNA

Filoviridae

Orlhomyxo viridae

Arenaviridae Bunyaviridae

Reoviridae

Retrovindae

1dsRNA

reverse

J cleaved spliced cleaved

Fig. 3-5 Simplified d iagram showing essential features of the replication of RNA viruses The sense of each nucleic acid molecule is indicated by an arrow ( l- to the right, - to the left; - , + for Atenmnrufoe and Bmit/aviridae indicates ambisense RNA in one segment) t, Segmented genome, 2, diploic) genome of Relroviridac For simplicity, the number ol mRNA moleculcs and protein molecules has been arbitrarily shown as four, as have the number of segments in viruses with segmented genomes See text for details into a complementary (minus sense) copy, which in turn serves as a template for the synthesis (if plus strand (viral) RNA.

Only about two-thirds of the viral RNA (the 5' end) of togaviruses is translated The resulting polyprotein is cleaved into nonstructural proteins, all of which are required for RNA transcription and replication. Viral RNA polymerase makes a full-length minus strand, from which two species of plus strands are copied: full-length virion RNA, destined for encapsidation, and a one-third length RNA, which is colinear with the 3' terminus of the viral RNA and is translated into a polyprotein from which structural proteins are produced by cleavage. The caliciviruses have not been so extensively studied but also produce both genome-length and subgenomic mRNA species.

Coronaviruses

Initially, part of the plus sense virion RNA of coronaviruses is translated to produce an RNA polymerase, which then synthesizes a genome-length minus strand From this, a nested set of overlapping subgenomic mRNAs with a common 3'-termination site is transcribed. Only the unique 5'-terminal sequence of each successive member of the set of overlapping transcripts is translated.

Paramyxoviruses, Rhabdoviruses, Filoviruscs

The minus sense, nonsegmented ssRNA viruses of the families Paramyx-avirtdae, Rhctbdovmdae, and FUoviridae carry an RNA-dependent RNA polymerase (transcriptase), which transcribes five or more subgenomic plus sense RNAs, each of which serves as a monocistronic mRNA. In contrast, transcription in the replication mode (by the replicase) produces a full-length plus strand which is used as the template for the synthesis of new viral RNA.

Orthomyxoviruses, Bunyaviruses, Arenaviruses

The minus sense RNA viruses of the families Orthomyxoviridae, Bun-yavtridae, and Arenaviridae have segmented genomes, each segment of which is transcribed by a transcriptase carried in the virion to yield an mRNA which is translated into one or more proteins. In the case of the orthomyxoviruses, most of the segments encode single proteins. Furthermore, the ssRNA genome of arenaviruses and certain genera of bunyaviruses is ambisense, that is, part plus sense and part minus sense. The replication strategy of ambisense RNA viruses, like the sense of their genomes, is mixed, with features of both plus sense and minus sense ssRNA viruses

Reoviruses

Viruses of the family Rcovindae have segmented dsRNA genomes. The minus strand of each segment is separately transcribed in the cytoplasm by a virion-associated transcriptase to produce mRNA. These plus sense RNAs also serve as templates for replication. The resulting dsRNA in turn serves as the template for further mRNA transcription

Retroviruses

In the retroviruses the viral RNA is plus sense, but instead of functioning as mRNA it is transcribed by a viral RNA-dependent DNA polymerase (re verse transcriptase) to produce first an RNA-DNA hybrid molecule, which is in turn converted to dsDNA (by another activity of the same enzyme) and inserted permanently into cellular DNA This integrated viral DNA (provirus) is subsequently transcribed by cellular RNA polymerase II, followed by splicing of the RNA transcript as well as cleavage of the resulting proteins. Some lull-length positive sense RNA transcripts associate in pairs to form the diploid genomes of new virions

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