title: The expression of a viral microRNA is regulated by clustering to allow optimal B cell transformation.
abstract: The Epstein-Barr virus (EBV) transforms B cells by expressing latent proteins and the BHRF1 microRNA cluster. MiR-BHRF1-3, its most transforming member, belongs to the recently identified group of weakly expressed microRNAs. We show here that miR-BHRF1-3 displays an unusually low propensity to form a stem-loop structure, an effect potentiated by miR-BHRF1-3's proximity to the BHRF1 polyA site. Cloning miR-BHRF1-2 or a cellular microRNA, but not a ribozyme, 5' of miR-BHRF1-3 markedly enhanced its expression. However, a virus carrying mutated miR-BHRF1-2 seed regions expressed miR-BHRF1-3 at normal levels and was fully transforming. Therefore, miR-BHRF1-2's role during transformation is independent of its seed regions, revealing a new microRNA function. Increasing the distance between miR-BHRF1-2 and miR-BHRF1-3 in EBV enhanced miR-BHRF1-3's expression but decreased its transforming potential. Thus, the expression of some microRNAs must be restricted to a narrow range, as achieved by placing miR-BHRF1-3 under the control of miR-BHRF1-2.
authors.affiliation: Pathogenesis of Virus Associated Tumors, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany Inserm unit U1074, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
authors.forename: Janina
authors.initials: J
authors.lastname: Haar
authors.affiliation: Architecture et Réactivité de l'ARN - UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 15 rue René Descartes, F-67084 Strasbourg Cedex, France.
authors.forename: Maud
authors.initials: M
authors.lastname: Contrant
authors.affiliation: Pathogenesis of Virus Associated Tumors, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany Inserm unit U1074, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
authors.forename: Katharina
authors.initials: K
authors.lastname: Bernhardt
authors.affiliation: Pathogenesis of Virus Associated Tumors, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany Inserm unit U1074, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Feederle
authors.affiliation: Division of Cancer Research, Clinic for Thoracic Surgery, University Hospital Freiburg, Breisacher Str. 86b, 79110 Freiburg, Germany Division of RNA Biology & Cancer, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany & Institute of Pathology, University Hospital Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors.forename: Sven
authors.initials: S
authors.lastname: Diederichs
authors.affiliation: Architecture et Réactivité de l'ARN - UPR 9002, Institut de Biologie Moléculaire et Cellulaire du CNRS, Université de Strasbourg, 15 rue René Descartes, F-67084 Strasbourg Cedex, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Pfeffer
authors.affiliation: Pathogenesis of Virus Associated Tumors, German Cancer Research Center, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany Inserm unit U1074, Im Neuenheimer Feld 242, 69120 Heidelberg, Germany h.delecluse@dkfz-heidelberg.de.
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
mesh_terms: D001402:B-Lymphocytes / Q000821:virology; D001483:Base Sequence; D015152:Blotting, Northern; D015153:Blotting, Western; D002460:Cell Line; D045744:Cell Line, Tumor; D002472:Cell Transformation, Viral / Q000235:genetics*; D002478:Cells, Cultured; D015967:Gene Expression Regulation, Viral; D057809:HEK293 Cells; D004854:Herpesvirus 4, Human / Q000235:genetics* / Q000378:metabolism / Q000502:physiology; D054884:Host-Pathogen Interactions; D006801:Humans; D035683:MicroRNAs / Q000737:chemistry / Q000235:genetics*; D008958:Models, Molecular; D005810:Multigene Family; D009690:Nucleic Acid Conformation; D012367:RNA, Viral / Q000737:chemistry / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014764:Viral Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C083278:BHRF1 protein, Human herpesvirus 4; D035683:MicroRNAs; D012367:RNA, Viral; D014764:Viral Proteins