title: Molecular basis of the attenuated phenotype of human APOBEC3B DNA mutator enzyme.
abstract: The human APOBEC3A and APOBEC3B genes (A3A and A3B) encode DNA mutator enzymes that deaminate cytidine and 5-methylcytidine residues in single-stranded DNA (ssDNA). They are important sources of mutations in many cancer genomes which show a preponderance of CG->TA transitions. Although both enzymes can hypermutate chromosomal DNA in an experimental setting, only A3A can induce double strand DNA breaks, even though the catalytic domains of A3B and A3A differ by only 9% at the protein level. Accordingly we sought the molecular basis underlying A3B attenuation through the generation of A3A-A3B chimeras and mutants. It transpires that the N-terminal domain facilitates A3B activity while a handful of substitutions in the catalytic C-terminal domain impacting ssDNA binding serve to attenuate A3B compared to A3A. Interestingly, functional attenuation is also observed for the rhesus monkey rhA3B enzyme compared to rhA3A indicating that this genotoxic dichotomy has been selected for and maintained for some 38 million years. Expression of all human ssDNA cytidine deaminase genes is absent in mature sperm indicating they contribute to somatic mutation and cancer but not human diversity.
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: 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: Rodolphe
authors.initials: R
authors.lastname: Suspène
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: Human Developmental Genetics Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Marie-Charlotte
authors.initials: MC
authors.lastname: Dumargne
authors.affiliation: Human Developmental Genetics Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Anu
authors.initials: A
authors.lastname: Bashamboo
authors.affiliation: Structural Virology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Krey
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
authors.affiliation: Molecular Retrovirology Unit, Institut Pasteur, 28 rue du Dr. Roux, 75724 Paris cedex 15, France simon.wain-hobson@pasteur.fr.
authors.forename: Simon
authors.initials: S
authors.lastname: Wain-Hobson
mesh_terms: D000818:Animals; D002460:Cell Line; D003564:Cytidine Deaminase / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D053903:DNA Breaks, Double-Stranded; D006367:HeLa Cells; D006801:Humans; D008253:Macaca mulatta; D015778:Minor Histocompatibility Antigens; D009154:Mutation; D010641:Phenotype; D017434:Protein Structure, Tertiary; D011506:Proteins / Q000737:chemistry / Q000235:genetics; D011784:Quail; D017393:RNA Editing
chemical_list: D015778:Minor Histocompatibility Antigens; D011506:Proteins; C121399:APOBEC3A protein, human; C495794:APOBEC3B protein, human; D003564:Cytidine Deaminase