APOBEC3 genes: retroviral restriction factors to cancer drivers

•APOBEC3 (A3) enzymes deaminate single-stranded DNA, mutating viral genomes.•Tumors harbor mutations likely due to off-target A3 deamination of chromosomal DNA.•A common APOBEC3 deletion polymorphism increases breast cancer risk.•A growing body of evidence points to a driver role for APOBEC3s in tumorigenesis.

The APOBEC3 cytosine deaminases play key roles in innate immunity through their ability to mutagenize viral DNA and restrict viral replication. Recent advances in cancer genomics, together with biochemical characterization of the APOBEC3 enzymes, have now implicated at least two family members in somatic mutagenesis during tumor development. We review the evidence linking these enzymes to carcinogenesis and highlight key questions, including the potential mechanisms that misdirect APOBEC3 activity to the host genome, the links to viral infection, and the association between a common APOBEC3 polymorphism and cancer risk.