Cis and trans requirements for stable episomal maintenance of the BPV‐1 replicator.

Papillomavirus genomes are maintained as multicopy nuclear plasmids in transformed cells. To address the mechanisms by which the viral DNA is stably propagated in the transformed cells, we have constructed a cell line CH04.15 expressing constitutively the viral proteins E1 and E2, that are required for initiation of viral DNA replication. We show that these viral proteins are necessary and sufficient for stable extrachromosomal replication. Using the cell line CH04.15, we have shown that the bovine papillomavirus‐1 (BPV‐1) minimal origin of replication (MO) is absolutely necessary, but is not sufficient for stable extrachromosomal replication of viral plasmids. By deletion and insertion analysis, we identified an additional element (minichromosome maintenance element, MME) in the upstream regulatory region of BPV‐1 which assures stable replication of the MO‐containing plasmids. This element is composed of multiple binding sites for the transcription activator E2. MME appears to function in the absence of replication but requires E1 and E2 proteins for activity. In contrast to, for example, Epstein‐Barr virus oriP, stably maintained BPV‐1 plasmids are not subject to once‐per‐cell cycle replication as determined by density labelling experiments. These results indicate that papillomavirus episomal replicators replicate independently of the chromosomal DNA of their hosts.

[1]  C. Bonne-Andrea,et al.  Bovine papillomavirus E1 protein can, by itself, efficiently drive multiple rounds of DNA synthesis in vitro , 1995, Journal of virology.

[2]  A. Kirchmaier,et al.  Plasmid maintenance of derivatives of oriP of Epstein-Barr virus , 1995, Journal of virology.

[3]  M. Botchan,et al.  cis-Acting components of human papillomavirus (HPV) DNA replication: linker substitution analysis of the HPV type 11 origin , 1995, Journal of virology.

[4]  F. Sverdrup,et al.  Two E2 binding sites alone are sufficient to function as the minimal origin of replication of human papillomavirus type 18 DNA , 1995, Journal of virology.

[5]  T. R. Broker,et al.  Cell-free replication of the human papillomavirus DNA with homologous viral E1 and E2 proteins and human cell extracts. , 1994, The Journal of biological chemistry.

[6]  J. Hurwitz,et al.  Replication of bovine papillomavirus type 1 origin-containing DNA in crude extracts and with purified proteins. , 1994, The Journal of biological chemistry.

[7]  B. Sugden,et al.  Retention of plasmid DNA in mammalian cells is enhanced by binding of the Epstein-Barr virus replication protein EBNA1 , 1994, Journal of virology.

[8]  D. McCance,et al.  Two E2 binding sites (E2BS) alone or one E2BS plus an A/T-rich region are minimal requirements for the replication of the human papillomavirus type 11 origin , 1993, Journal of virology.

[9]  P. Lambert,et al.  The 23-kilodalton E1 phosphoprotein of bovine papillomavirus type 1 is nonessential for stable plasmid replication in murine C127 cells , 1993, Journal of virology.

[10]  M. Ustav,et al.  The bovine papillomavirus origin of replication requires a binding site for the E2 transcriptional activator. , 1993, Proceedings of the National Academy of Sciences of the United States of America.

[11]  M. DePamphilis Eukaryotic DNA replication: anatomy of an origin. , 1993, Annual review of biochemistry.

[12]  D. Gilbert,et al.  Random-choice replication of extrachromosomal bovine papillomavirus (BPV) molecules in heterogeneous, clonally derived BPV-infected cell lines , 1992, Journal of virology.

[13]  T. R. Broker,et al.  Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[14]  P. Howley,et al.  The bovine papillomavirus constitutive enhancer is essential for viral transformation, DNA replication, and the maintenance of latency , 1992, Journal of virology.

[15]  M. Ustav,et al.  Identification of the origin of replication of bovine papillomavirus and characterization of the viral origin recognition factor E1. , 1991, The EMBO journal.

[16]  A. Stenlund,et al.  Regulation of early gene expression from the bovine papillomavirus genome in transiently transfected C127 cells , 1991, Journal of virology.

[17]  M. Botchan,et al.  Activation of BPV-1 replication in vitro by the transcription factor E2 , 1991, Nature.

[18]  M. Ustav,et al.  Transient replication of BPV‐1 requires two viral polypeptides encoded by the E1 and E2 open reading frames. , 1991, The EMBO journal.

[19]  G. Wahl,et al.  A central role for chromosome breakage in gene amplification, deletion formation, and amplicon integration. , 1991, Genes & development.

[20]  J. Yates,et al.  Epstein-Barr virus-derived plasmids replicate only once per cell cycle and are not amplified after entry into cells , 1991, Journal of virology.

[21]  M. Botchan,et al.  Targeting the E1 replication protein to the papillomavirus origin of replication by complex formation with the E2 transactivator. , 1990, Science.

[22]  K. Nordström Control of plasmid replication—How do DNA iterons set the replication frequency? , 1990, Cell.

[23]  T. Kelly,et al.  Reconstitution of simian virus 40 DNA replication with purified proteins. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[24]  B. Stillman,et al.  Sequential initiation of lagging and leading strand synthesis by two different polymerase complexes at the SV40 DNA replication origin , 1990, Nature.

[25]  J. Diffley,et al.  The initiation of chromosomal DNA replication in eukaryotes. , 1990, Trends in genetics : TIG.

[26]  E. de Villiers Heterogeneity of the human papillomavirus group , 1989, Journal of virology.

[27]  M. Botchan,et al.  Specific recognition nucleotides and their DNA context determine the affinity of E2 protein for 17 binding sites in the BPV-1 genome. , 1989, Genes & development.

[28]  G. Wahl,et al.  The importance of circular DNA in mammalian gene amplification. , 1989, Cancer research.

[29]  S. Haase,et al.  Isolation of human sequences that replicate autonomously in human cells , 1989, Molecular and cellular biology.

[30]  Stanley N Cohen,et al.  Bovine papilloma virus plasmids replicate randomly in mouse fibroblasts throughout S phase of the cell cycle , 1987, Cell.

[31]  P. Howley,et al.  Bovine papillomavirus transcriptional regulation: localization of the E2-responsive elements of the long control region , 1987, Journal of Virology.

[32]  M. Botchan,et al.  A bovine papillomavirus type 1-encoded modulator function is dispensable for transient viral replication but is required for establishment of the stable plasmid state , 1986, Journal of virology.

[33]  M. Botchan,et al.  Repression of bovine papilloma virus replication is mediated by a virally encoded Trans-acting factor , 1986, Cell.

[34]  James M. Roberts,et al.  Negative control of DNA replication in composite SV40-bovine papilloma virus plasmids , 1986, Cell.

[35]  M. Botchan,et al.  The bovine papillomavirus replicon. , 1986, Ciba Foundation symposium.

[36]  J. Yates,et al.  Stable replication of plasmids derived from Epstein–Barr virus in various mammalian cells , 1985, Nature.

[37]  D. Reisman,et al.  A cis-acting element from the Epstein-Barr viral genome that permits stable replication of recombinant plasmids in latently infected cells. , 1984, Proceedings of the National Academy of Sciences of the United States of America.

[38]  M. Botchan,et al.  Characterization of the Bovine Papilloma virus plasmid maintenance sequences , 1984, Cell.

[39]  D. Lowy,et al.  Mouse cells transformed by bovine papillomavirus contain only extrachromosomal viral DNA sequences. , 1981, Proceedings of the National Academy of Sciences of the United States of America.

[40]  R. W. Davis,et al.  High-frequency transformation of yeast: autonomous replication of hybrid DNA molecules. , 1979, Proceedings of the National Academy of Sciences of the United States of America.

[41]  François Jacob,et al.  On the Regulation of DNA Replication in Bacteria , 1963 .