title: Self-cytoplasmic DNA upregulates the mutator enzyme APOBEC3A leading to chromosomal DNA damage.
abstract: Foreign and self-cytoplasmic DNA are recognized by numerous DNA sensor molecules leading to the production of type I interferons. Such DNA agonists should be degraded otherwise cells would be chronically stressed. Most human APOBEC3 cytidine deaminases can initiate catabolism of cytoplasmic mitochondrial DNA. Using the human myeloid cell line THP-1 with an interferon inducible APOBEC3A gene, we show that cytoplasmic DNA triggers interferon α and β production through the RNA polymerase III transcription/RIG-I pathway leading to massive upregulation of APOBEC3A. By catalyzing C→U editing in single stranded DNA fragments, the enzyme prevents them from re-annealing so attenuating the danger signal. The price to pay is chromosomal DNA damage in the form of CG→TA mutations and double stranded DNA breaks which, in the context of chronic inflammation, could drive cells down the path toward cancer.
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Suspène
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.|Unit of Infection Models, German Primate Centre, Kellnerweg 4, 37077 Goettingen, Germany.
authors.forename: Bianka
authors.initials: B
authors.lastname: Mussil
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Hélène
authors.initials: H
authors.lastname: Laude
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Vincent
authors.initials: V
authors.lastname: Caval
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Noémie
authors.initials: N
authors.lastname: Berry
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Mohamed S
authors.initials: MS
authors.lastname: Bouzidi
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Valérie
authors.initials: V
authors.lastname: Thiers
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Simon
authors.initials: S
authors.lastname: Wain-Hobson
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vartanian
mesh_terms: D045744:Cell Line, Tumor; D002877:Chromosomes, Human; D003564:Cytidine Deaminase / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D003600:Cytosol / Q000378:metabolism; D000071457:DEAD Box Protein 58; D053903:DNA Breaks, Double-Stranded; D004272:DNA, Mitochondrial / Q000737:chemistry / Q000378:metabolism*; D006801:Humans; D016898:Interferon-alpha / Q000096:biosynthesis; D016899:Interferon-beta / Q000096:biosynthesis / Q000502:physiology; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D012320:RNA Polymerase III / Q000378:metabolism; D011971:Receptors, Immunologic; D014158:Transcription, Genetic; D015854:Up-Regulation; D014498:Uracil / Q000378:metabolism
chemical_list: D004272:DNA, Mitochondrial; D016898:Interferon-alpha; D011506:Proteins; D011971:Receptors, Immunologic; D014498:Uracil; D016899:Interferon-beta; D012320:RNA Polymerase III; C121399:APOBEC3A protein, human; D003564:Cytidine Deaminase; C452820:RIGI protein, human; D000071457:DEAD Box Protein 58