Members of the APOBEC (apolipoprotein B mRNA editing enzyme, catalytic 
polypeptide-like) protein family catalyze DNA cytosine deamination and underpin 
a variety of immune defenses. For instance, several family members, including 
APOBEC3B (A3B), elicit strong retrotransposon and retrovirus restriction 
activities. However, unlike the other proteins, A3B is the only family member 
with steady-state nuclear localization. Here, we show that A3B nuclear import is 
an active process requiring at least one amino acid (Val54) within an N-terminal 
motif analogous to the nuclear localization determinant of the antibody gene 
diversification enzyme AID (activation-induced cytosine deaminase). Mechanistic 
conservation with AID is further suggested by A3B's capacity to interact with 
the same subset of importin proteins. Despite these mechanistic similarities, 
enforced A3B expression cannot substitute for AID-dependent antibody gene 
diversification by class switch recombination. Regulatory differences between 
A3B and AID are also visible during cell cycle progression. Our studies suggest 
that the present-day A3B enzyme retained the nuclear import mechanism of an 
ancestral AID protein during the expansion of the APOBEC3 locus in primates. Our 
studies also highlight the likelihood that, after nuclear import, specialized 
mechanisms exist to guide these enzymes to their respective physiological 
substrates and prevent gratuitous chromosomal DNA damage.