title: Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A.
abstract: The human polydeoxynucleotide cytidine deaminases APOBEC3A, APOBEC3C, and APOBEC3H are capable of mutating viral DNA in the nucleus, whereas APOBEC3A alone efficiently edits nuclear DNA. Deamination is rapidly followed by excision of uracil residues and can lead to double-stranded breaks. It is not known to which protein networks these DNA mutators belong. Using a yeast two-hybrid screen, we identified the human homolog of Drosophila Tribbles 3, TRIB3, as an interactor for APOBEC3A and APOBEC3C. The interaction was confirmed by co-affinity purification. Co-transfection of APOBEC3A with a TRIB3 expression vector reduced nuclear DNA editing whereas siRNA knockdown of TRIB3 increased the levels of nuclear DNA editing, indicating that TRIB3 functioned as a repressor of A3A. It also repressed A3A-associated γH2AX positive double-stranded breaks. The interaction results in degradation of A3A in a proteasome-independent manner. TRIB3 has been linked to cancer and via its own interactors and links the A3A DNA mutators to the Rb-BRCA1-ATM network. TRIB3 emerges as an important guardian of genome integrity.
authors.affiliation: Molecular Retrovirology Unit, CNRS URA3015, Institut Pasteur, 28 rue du Dr Roux, F-75724 Paris cedex 15, France.
authors.forename: Marie-Ming
authors.initials: MM
authors.lastname: Aynaud
authors.forename: Rodolphe
authors.initials: R
authors.lastname: Suspène
authors.forename: Pierre-Olivier
authors.initials: PO
authors.lastname: Vidalain
authors.forename: Bianka
authors.initials: B
authors.lastname: Mussil
authors.forename: Denise
authors.initials: D
authors.lastname: Guétard
authors.forename: Frédéric
authors.initials: F
authors.lastname: Tangy
authors.forename: Simon
authors.initials: S
authors.lastname: Wain-Hobson
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Vartanian
mesh_terms: D002453:Cell Cycle; D002467:Cell Nucleus / Q000378:metabolism*; D002470:Cell Survival; D003562:Cytidine / Q000737:chemistry*; D003564:Cytidine Deaminase / Q000378:metabolism* / Q000502:physiology; D004247:DNA / Q000378:metabolism*; D004260:DNA Repair; D003641:Deamination; D005786:Gene Expression Regulation; D016678:Genome; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D018613:Microscopy, Confocal / Q000379:methods; D016296:Mutagenesis; D009154:Mutation; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011506:Proteins / Q000378:metabolism* / Q000502:physiology; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D011506:Proteins; D016271:Proto-Oncogene Proteins c-myc; D003562:Cytidine; D004247:DNA; D046988:Proteasome Endopeptidase Complex; C121399:APOBEC3A protein, human; C495795:APOBEC3C protein, human; D003564:Cytidine Deaminase