Article

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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    • "These APOBEC3 mutator enzymes must be tightly controlled as at least four (A3A, A3B, A3C and A3H) can access the nucleus (Vartanian et al, 2008; Stenglein et al, 2010; Landry et al, 2011; Suspène et al, 2011a; Aynaud et al, 2012; Shinohara et al, 2012; Burns et al, 2013a, b). More recently, it has emerged that APOBEC3A (A3A) and probably APOBEC3B (A3B) can mutate nuclear DNA (nuDNA) (Suspène et al, 2011a; Aynaud et al, 2012; Shinohara et al, 2012; Burns et al, 2013a). A3A can edit both cytidine and 5-methylcytidine residues in ssDNA (Carpenter et al, 2012; Wijesinghe and Bhagwat, 2012; Suspène et al, 2013) and can generate DNA double-strand breaks (Landry et al, 2011; Mussil et al, 2013). "
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    • "Following cytidine deamination of nuDNA, UNG excision of uracil bases and subsequent APE1 cleavage of the DNA backbone at abasic sites can result in DSBs characterized by gH2AX phosphorylation (Rogakou et al. 1998). Although well established for AID, it has recently been shown to occur following human A3A deamination (Landry et al. 2011; Aynaud et al. 2012). As most mammalian A3A enzymes can deaminate, nuDNA induction of gH2AX positive DSBs was assessed for all A3A proteins. "
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