Human Tribbles 3 protects nuclear DNA from cytidine deamination by APOBEC3A.

Institut Pasteur, France.
Journal of Biological Chemistry (Impact Factor: 4.6). 09/2012; DOI: 10.1074/jbc.M112.372722
Source: PubMed

ABSTRACT The human polydeoxynucleotide cytidine deaminases APOBEC3A, APOBEC3C and APOBEC3H are capable of mutating viral DNA in the nucleus, while APOBEC3A alone efficiently edits nuclear DNA. Deamination is rapidly followed by excision of uracil residues and can lead to double strand breaks. It is not known to which protein networks these DNA mutators belong. Using a yeast two-hybrid screen, we identified the human homologue 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 while 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 strand breaks. The interaction results in degradation of A3A in a proteasome independent manner. TRIB3 has been linked to cancer and via it own interactors, links the A3A DNA mutators to the Rb-BRCA1-ATM network. TRIB3 emerges as an important guardian of genome integrity.

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