title: The cellular protein MCM3AP is required for inhibition of cellular DNA synthesis by the IE86 protein of human cytomegalovirus.
abstract: Like all DNA viruses, human cytomegalovirus (HCMV) infection is known to result in profound effects on host cell cycle. Infection of fibroblasts with HCMV is known to induce an advance in cell cycle through the G(0)-G(1) phase and then a subsequent arrest of cell cycle in early S-phase, presumably resulting in a cellular environment optimum for high levels of viral DNA replication whilst precluding replication of cellular DNA. Although the exact mechanisms used to arrest cell cycle by HCMV are unclear, they likely involve a number of viral gene products and evidence points to the ability of the virus to prevent licensing of cellular DNA synthesis. One viral protein known to profoundly alter cell cycle is the viral immediate early 86 (IE86) protein--an established function of which is to initially drive cells into early S phase but then inhibit cellular DNA synthesis. Here we show that, although IE86 interacts with the cellular licensing factor Cdt1, it does not inhibit licensing of cellular origins. Instead, IE86-mediated inhibition of cellular DNA synthesis requires mini-chromosome-maintenance 3 (MCM3) associated protein (MCM3AP), which can cause subsequent inhibition of initiation of cellular DNA synthesis in a licensing-independent manner.
authors.affiliation: Department of Medicine, Addenbrooke's Hospital, University of Cambridge, Cambridge, United Kingdom.
authors.forename: Emma
authors.initials: E
authors.lastname: Poole
authors.forename: Mark
authors.initials: M
authors.lastname: Bain
authors.forename: Linda
authors.initials: L
authors.lastname: Teague
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Takei
authors.forename: Ron
authors.initials: R
authors.lastname: Laskey
authors.forename: John
authors.initials: J
authors.lastname: Sinclair
mesh_terms: D000123:Acetyltransferases / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D059447:Cell Cycle Checkpoints / Q000235:genetics*; D002478:Cells, Cultured; D003587:Cytomegalovirus / Q000502:physiology*; D004261:DNA Replication; D005347:Fibroblasts / Q000378:metabolism* / Q000821:virology*; D015870:Gene Expression; D057809:HEK293 Cells; D054884:Host-Pathogen Interactions; D006801:Humans; D017874:Immediate-Early Proteins / Q000235:genetics*; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors / Q000235:genetics* / Q000378:metabolism; D010957:Plasmids; D034741:RNA, Small Interfering / Q000235:genetics; D015534:Trans-Activators / Q000235:genetics*; D014162:Transfection; D014779:Virus Replication
chemical_list: C069186:IE2 protein, Cytomegalovirus; D017874:Immediate-Early Proteins; D047908:Intracellular Signaling Peptides and Proteins; D034741:RNA, Small Interfering; D015534:Trans-Activators; D000123:Acetyltransferases; C406825:MCM3AP protein, human