Much of the impetus for studying the replication of animal virus genomes comes from a desire to understand the events that occur during the replication of eukaryotic chromosomes. Viruses offer many advantages for the study of eukaryotic DNA replication. Viral genomes are relatively simple and can be readily manipulated by modern genetic methods. In addition, the replication of some viral genomes has proven amenable to analysis in cell-free systems. These facts significantly enhance the ability to analyse replication mechanisms at the molecular level. There are a number of potentially useful viral systems, and this review focuses on four of the best characterized: (a) adenovirus, (b) SV40, (c) herpes simplex virus, and (d) bovine papillomavirus. Each system has certain unique virtues that can be exploited to gain insight into different aspects of the replication process. Adenovirus DNA replication occurs by a process that is significantly less complex than chromosomal DNA replication. Replication initiates by a novel protein priming mechanism, and all daughter strands are elongated by a continuous mode of synthesis such as occurs at the leading strand of a chromosomal replication fork. The biochemical dissection of a soluble in vitro system capable of faithfully replicating adenovirus DNA has led to the identification of most of the proteins involved. Adenovirus DNA replication requires the participation both of virus-encoded replication proteins and host-cell-encoded transcription factors. Since a linkage between replication and transcription has now been observed in other systems, it is likely that further analysis of the adenovirus system will provide insights that are of general importance. The SV40 genome represents a more complete model system for studying cellular DNA replication. SV40 encodes only a single replication protein (T antigen) and relies predominantly on the host-cell replication machinery. In vivo studies have established that many of the details of SV40 DNA replication are closely similar to those of cellular DNA replication. Replication initiates at a fixed site on the viral genoma and proceeds bidirectionally with continuous growth of leading strands and discontinuous growth of lagging strand. As in the case of adenovirus, an efficient cell-free replication system has been developed for SV40, and dissection of this system has identified several cellular replication proteins. A partial understanding of the mechanisms by which these proteins act is beginning to emerge, and it seems certain that this will be an area of continued rapid progress. In contrast to SV40, herpes simplex virus (HSV) encodes many, if not all, of the proteins that are involved in the replication of its genome. Thus, HSV DNA replication has been studied by using a combination of genetics and biochemistry. The complete set of viral genes necessary for DNA synthesis has recently been identified, and the products of many of these genes have been purified and partially characterized. Several of these purified protiens have functions expected of replication proteins, including a DNA polymerase, a helicase, a primase, a single-stranded DNA binding protein, and an origin recognition protein. It seems likely that the availability of these purified proteins will soon lead to the development of an in vitro system capable of specifically replicating HSV DNA. Genetic and biochemical dissection of such a system should provide important new insights into the molecular mechanisms of eukaryotic DNA replication. Adenovirus, SV40, and HSV are all examples of viruses that normally multiply by productive cytocidal infection. In all of these cases, viral DNA replication begins soon after infection and continues at a high rate until the death of the host cell. In contrast, bovine papillomavirus (BPV) represents an example of a virus that is capable of multiplying as a stable extrachromosomal element. In this case, viral DNA replication is controlled so that the number of viral genomes doubles only once per cell cycle, and under normal circumstances the host is not killed. As in the case of SV40, the BPV genome is relatively small and encodes only a small number of proteins involved in DNA replication; viral DNA synthesis depends heavily on host-cell replication proteins. The biochemical analysis of BPV DNA replication is in its infancy, but genetic analyses have provided evidence for a negative control system that apparently ensures that each viral genome is replicated once and only once during each cell cycle. Bovine papillomavirus therefore represents an excellent model for illuminating mechanisms involved in regulating DNA replication.
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