title: Vpr expression abolishes the capacity of HIV-1 infected cells to repair uracilated DNA.
abstract: The human immunodeficiency virus type 1 (HIV-1) Vpr protein binds to the cellular uracil-DNA glycosylase UNG2 and induces its degradation through the assembly with the DDB1-CUL4 ubiquitin ligase complex. This interaction counteracts the antiviral activity exerted by UNG2 on HIV-1 gene transcription, as previously reported by us. In this work, we show that Vpr expression in the context of HIV-1 infection markedly decreases UNG2 expression in transformed or primary CD4(+) T lymphocytes. We demonstrate for the first time that Vpr-UNG2 interaction significantly impairs the uracil excision activity of infected cells. The loss of uracil excision activity coincides with a significant accumulation of uracilated bases in the genome of infected cells without changes in cell division. Although UNG2 expression and uracil-DNA glycosylase activity are recovered after the peak of retroviral replication, the mutagenic effect of transient DNA uracilation in cycling cells should be taken into account. Therefore, the possible consequences of Vpr-mediated temporary depletion of endogenous nuclear UNG2 and subsequent alteration of the genomic integrity of infected cells need to be evaluated in the physiopathogenesis of HIV infection.
authors.affiliation: Centre d'étude d'agents Pathogènes et Biotechnologies pour la Santé (CPBS) - UMR 5236-CNRS - Université Montpellier 1 and 2, Montpellier, France and Centre de Biochimie Structurale, INSERM U1054, CNRS UMR5048, Université Montpellier 1 and 2, Montpellier, France.
authors.forename: Patrick
authors.initials: P
authors.lastname: Eldin
authors.forename: Nathalie
authors.initials: N
authors.lastname: Chazal
authors.forename: David
authors.initials: D
authors.lastname: Fenard
authors.forename: Eric
authors.initials: E
authors.lastname: Bernard
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Guichou
authors.forename: Laurence
authors.initials: L
authors.lastname: Briant
mesh_terms: D015496:CD4-Positive T-Lymphocytes / Q000201:enzymology / Q000821:virology; D002453:Cell Cycle; D002460:Cell Line; D002470:Cell Survival; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D045647:DNA Glycosylases / Q000378:metabolism*; D004260:DNA Repair; D057075:Enzyme Assays / Q000379:methods; D015497:HIV-1 / Q000502:physiology*; D006801:Humans; D014498:Uracil / Q000378:metabolism; D054325:vpr Gene Products, Human Immunodeficiency Virus / Q000378:metabolism*
chemical_list: D054325:vpr Gene Products, Human Immunodeficiency Virus; C514912:vpr protein, Human immunodeficiency virus 1; D014498:Uracil; D004247:DNA; C492570:CCNO protein, human; D045647:DNA Glycosylases