Identification of an arginine-rich motif in human papillomavirus type 1 E1^E4 protein necessary for E4-mediated inhibition of cellular DNA Synthesis In Vitro and in Cells

2.50
Hdl Handle:
http://hdl.handle.net/10545/274392
Title:
Identification of an arginine-rich motif in human papillomavirus type 1 E1^E4 protein necessary for E4-mediated inhibition of cellular DNA Synthesis In Vitro and in Cells
Authors:
Roberts, Sally; Kingsbury, S. R.; Stoeber, K.; Knight, Gillian L. ( 0000-0001-5334-2491 ) ; Gallimore, P. H.; Williams, G. H.
Abstract:
Productive infections by human papillomaviruses (HPVs) are restricted to nondividing, differentiated keratinocytes. HPV early proteins E6 and E7 deregulate cell cycle progression and activate the host cell DNA replication machinery in these cells, changes essential for virus synthesis. Productive virus replication is accompanied by abundant expression of the HPV E4 protein. Expression of HPV1 E4 in cells is known to activate cell cycle checkpoints, inhibiting G2-to-M transition of the cell cycle and also suppressing entry of cells into S phase. We report here that the HPV1 E4 protein, in the presence of a soluble form of the replicationlicensing factor (RLF) Cdc6, inhibits initiation of cellular DNA replication in a mammalian cell-free DNA replication system. Chromatin-binding studies show that E4 blocks replication initiation in vitro by preventing loading of the RLFs Mcm2 and Mcm7 onto chromatin. HPV1 E4-mediated replication inhibition in vitro and suppression of entry of HPV1 E4-expressing cells into S phase are both abrogated upon alanine replacement of arginine 45 in the full-length E4 protein (E1^E4), implying that these two HPV1 E4 functions are linked. We hypothesize that HPV1 E4 inhibits competing host cell DNA synthesis in replication-activated suprabasal keratinocytes by suppressing licensing of cellular replication origins, thus modifying the phenotype of the infected cell in favor of viral genome amplification.
Citation:
Identification of an arginine-rich motif in human papillomavirus type 1 E1^E4 protein necessary for E4-mediated inhibition of cellular DNA Synthesis In Vitro and in Cells 2008, 82 (18):9056 Journal of Virology
Journal:
Journal of Virology
Issue Date:
20-Mar-2013
URI:
http://hdl.handle.net/10545/274392
DOI:
10.1128/JVI.01080-08
Additional Links:
http://jvi.asm.org/cgi/doi/10.1128/JVI.01080-08
Type:
Article
Description:
Effects of the HPV E4 protein has on cellular replication
ISSN:
0022-538X
Appears in Collections:
Biological Sciences Research Group

Full metadata record

DC FieldValue Language
dc.contributor.authorRoberts, Sallyen_GB
dc.contributor.authorKingsbury, S. R.en_GB
dc.contributor.authorStoeber, K.en_GB
dc.contributor.authorKnight, Gillian L.en_GB
dc.contributor.authorGallimore, P. H.en_GB
dc.contributor.authorWilliams, G. H.en_GB
dc.date.accessioned2013-03-20T15:05:06Z-
dc.date.available2013-03-20T15:05:06Z-
dc.date.issued2013-03-20-
dc.identifier.citationIdentification of an arginine-rich motif in human papillomavirus type 1 E1^E4 protein necessary for E4-mediated inhibition of cellular DNA Synthesis In Vitro and in Cells 2008, 82 (18):9056 Journal of Virologyen_GB
dc.identifier.issn0022-538X-
dc.identifier.doi10.1128/JVI.01080-08-
dc.identifier.urihttp://hdl.handle.net/10545/274392-
dc.descriptionEffects of the HPV E4 protein has on cellular replicationen_GB
dc.description.abstractProductive infections by human papillomaviruses (HPVs) are restricted to nondividing, differentiated keratinocytes. HPV early proteins E6 and E7 deregulate cell cycle progression and activate the host cell DNA replication machinery in these cells, changes essential for virus synthesis. Productive virus replication is accompanied by abundant expression of the HPV E4 protein. Expression of HPV1 E4 in cells is known to activate cell cycle checkpoints, inhibiting G2-to-M transition of the cell cycle and also suppressing entry of cells into S phase. We report here that the HPV1 E4 protein, in the presence of a soluble form of the replicationlicensing factor (RLF) Cdc6, inhibits initiation of cellular DNA replication in a mammalian cell-free DNA replication system. Chromatin-binding studies show that E4 blocks replication initiation in vitro by preventing loading of the RLFs Mcm2 and Mcm7 onto chromatin. HPV1 E4-mediated replication inhibition in vitro and suppression of entry of HPV1 E4-expressing cells into S phase are both abrogated upon alanine replacement of arginine 45 in the full-length E4 protein (E1^E4), implying that these two HPV1 E4 functions are linked. We hypothesize that HPV1 E4 inhibits competing host cell DNA synthesis in replication-activated suprabasal keratinocytes by suppressing licensing of cellular replication origins, thus modifying the phenotype of the infected cell in favor of viral genome amplification.en_GB
dc.relation.urlhttp://jvi.asm.org/cgi/doi/10.1128/JVI.01080-08en_GB
dc.rightsArchived with thanks to Journal of Virologyen_GB
dc.subjectHPVen_GB
dc.subjectCervical canceren_GB
dc.titleIdentification of an arginine-rich motif in human papillomavirus type 1 E1^E4 protein necessary for E4-mediated inhibition of cellular DNA Synthesis In Vitro and in Cells-
dc.typeArticleen
dc.identifier.journalJournal of Virologyen_GB
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