Identification of the origin of replication of bovine papillomavirus and characterization of the viral origin recognition factor E1.

Ustav, Mart; Ustav, Ene; Szymanski, Paul; Stenlund, Arne

doi:10.1002/j.1460-2075.1991.tb05010.x

Cited by 243 publications

(248 citation statements)

References 36 publications

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“…We also examined the abilities of matched or mixed combinations of the viral proteins to replicate the BPV-1 ori plasmid pUC/PstI (10). In agreement with previous reports, the homologous BPV-1 proteins were proficient in supporting BPV-1 ori replication (Fig.…”

Section: Resultssupporting

confidence: 85%

“…The minimal BPV-1 ori sequence is located at the 3' end of the upstream regulatory region (URR) within a 60-base-pair (bp) DNA fragment including an (A + T)-rich region, a consensus sequence to which all papillomaviral E2 proteins bind, and an El protein binding site spanning nucleotide (nt) 1 (9, 10). The El binding site is partially conserved among several papillomaviruses compared (9,10). The roles of the viral proteins in DNA replication are still under investigation.…”

mentioning

confidence: 99%

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Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins.

Chiang

Ustav

Stenlund

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

284

271

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We have shown that El and E2 proteins of human papillomavirus type 11 (HPV-11) were essential to support the replication of the homologous viral origin (on) in a transient replication assay, similar to reports on bovine papillomavirus type 1 (BPV-1). Unexpectedly, matched or even mixed combinations of El and E2 proteins from HPV-11 or BPV-l replicated either on in human, monkey, and rodent cell lines of epithelial or fibroblastic lineage, albeit with varied efficiencies. Either set of viral proteins was also able to initiate replication of ori-containing plasmids from many other human and animal papillomaviruses. Thus the interactions among the cis elements and trans factors of papillomaviruses are more conserved than expected from the other members of the papovavirus family, simian virus 40 and polyomavirus, for which large tumor antigen does not replicate a heterologous on in either permissive or nonpermissive cells. We infer that the stringent species and tissue specificities observed for papillomaviruses in vivo are not entirely due to direct restrictions on viral DNA replication. Rather, transcriptional control of viral gene expression must play a dominant role.The initiation of DNA replication occurs at precisely defined origins (ori) to which specific control proteins bind. Simian virus 40 (SV40) and polyomavirus have long been used as models for investigations of mammalian DNA replication. Initiation of SV40 or polyomavirus replication requires the homologous large tumor antigen, is species specific, and occurs only in a permissive cell environment (1-4). However, the uncontrolled replication of these lytic viruses does not reflect the precise regulation of cellular DNA replication, which takes place once per cell cycle in the S phase. In contrast, papillomaviruses have regulated and uncontrolled replication phases during their life cycle and therefore offer a unique opportunity to study eukaryotic DNA replication.Human papillomavirus (HPV) types trophic for mucosal epithelia, including HPV-11, are highly infectious pathogens that cause genital warts and laryngeal papillomatosis. A subset of the genital types, including HPV-16 and -18, is also associated with the development of neoplasia and progression to cancer. In subclinical or benign infections, viral DNA persists as low-copy-number plasmids in the nuclei of the undifferentiated basal stem cells. Productive replication takes place only in the more differentiated upper strata of the epithelium. Although a culture system has recently been developed in which preinfected tissues produce progeny HPV-11 virions (25), propagation of HPVs has not been achieved in vitro starting from virions or transfected DNA. In transfected or infected cells, HPV DNA either integrates into host chromosomes or is lost. Therefore it has not been possible, until now, to perform molecular studies of autonomous HPV DNA replication in cell culture.In contrast, bovine papillomavirus type 1 (BPV-1) in transformed rodent cell lines replicates extrachromosomally at a constan...

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Section: Resultssupporting

confidence: 85%

mentioning

confidence: 99%

Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins.

Chiang

Ustav

Stenlund

et al. 1992

Proc. Natl. Acad. Sci. U.S.A.

284

271

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“…Vectors for in vitro translation of full-length and truncated forms of BPV E1 and vectors for HPV1a E1 and HPV18 E1 were described previously (14,27,28). For in vivo experiments, NH 2 -terminally His-tagged E1 was expressed from pcDNA4/MAX (Invitrogen, Carlsbad, CA), untagged E1 was expressed from pCGE1 (29) for replication assays, and GFP-E1 was expressed from pEGFP-C2 (CLONTECH, Palo Alto, CA). All site-directed mutagenesis was carried out using the QuikChange polymerase chain reaction-based mutagenesis kit (Stratagene, La Jolla, CA), and the mutant plasmids were fully sequenced to exclude the possibility of second site mutations.…”

Section: Methodsmentioning

confidence: 99%

SUMO-1 Modification of Bovine Papillomavirus E1 Protein Is Required for Intranuclear Accumulation

Rangasamy¹,

Woytek²,

Khan³

et al. 2000

Journal of Biological Chemistry

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The E1 protein is a multifunctional, origin-binding helicase that is essential for replication of papillomaviruses. Recently, bovine papillomavirus E1 was shown to be post-translationally modified by the addition of the SUMO-1 polypeptide. Here we show that the site of sumoylation maps to lysine residue 514. This lysine and the flanking sequences are well conserved in human papillomavirus (HPV) E1 proteins. Both HPV1a and HPV18 E1 proteins are substrates for sumoylation in vitro, which is consistent with this modification being a general property of E1 proteins. Mutations, which impair the sumoylation of bovine papillomavirus E1, prevent normal nuclear accumulation of E1 with a concomitant loss of replication capacity. These results suggest that sumoylation plays a role in nuclear transport and could regulate the E1 replication function by controlling access to the nuclear replication domains. Bovine papillomavirus (BPV)1 E1 protein is the major initiator protein for viral DNA replication and thus plays a critical role in the establishment of episomal viral genomes in the host cell nucleus (1). E1 and E2 proteins are the only two viral proteins required to replicate the viral genome in vivo, whereas the rest of the replication machinery is provided by the host cell (2, 3). E1 is a DNA helicase that binds to specific sequences in the viral origin and unwinds the viral DNA for initiation of replication (4, 5). Purified E1 protein can initiate in vitro viral replication without the support of the E2 protein (6). However, the interaction of E1 with E2 protein promotes specific binding and assembly of E1 protein on the viral origin to form an active initiation complex (7,8). Additional functions of E1 include recruiting cellular replication factors, such as the DNA polymerase ␣ and replication protein A (9 -11). E1 also interacts with histone H1 (12) and SW1/SNF5 (13), suggesting that E1 plays a role in chromatin remodeling at the viral origin.Recently, we demonstrated that BPV E1 protein is posttranslationally modified by a novel process known as sumoylation (14). Sumoylation involves the covalent attachment of the small ubiquitin-related proteins (SUMO-1, -2, or -3) to target substrates (15). Sumoylation is achieved by a multistep process in a manner that is analogous to ubiquitinylation (reviewed in Ref. 16). SUMO is first activated by a heterodimeric enzyme termed Aos1/Uba2, and then the activated SUMO is covalently transferred to the SUMO-specific conjugating enzyme Ubc9 via a thioester linkage (17). Ubc9 physically interacts with various substrates and transfers SUMO to one or more lysine residues in the target protein. Unlike ubiquitinylation in which the primary function is targeting proteins for degradation, the effects of sumoylation are more substrate-specific and can result in alterations in function (18 -20), stability (21), or intracellular location (22-25) of the modified protein. For BPV E1, a mutant unable to interact with Ubc9 showed altered intranuclear distribution (14). As BPV E1 is the first kno...

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“…The E1 protein has site-specific DNA-binding functions and it binds to the origin of replication in the NCR (Ustav et al 1991;Holt et al 1994). The E2 open reading frame (ORF) encodes at least two or three different proteins which all act as transcription factors and regulate viral transcription (Cripe et al 1987;Baker et al 1987;Bouvard et al 1994).…”

Section: E1 and E2 Proteinsmentioning

confidence: 99%

Human papillomavirus type 16 in head and neck carcinogenesis

2005

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Identification of the origin of replication of bovine papillomavirus and characterization of the viral origin recognition factor E1.

Cited by 243 publications

References 36 publications

Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins.

Viral E1 and E2 proteins support replication of homologous and heterologous papillomaviral origins.

SUMO-1 Modification of Bovine Papillomavirus E1 Protein Is Required for Intranuclear Accumulation

Human papillomavirus type 16 in head and neck carcinogenesis

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