A3 signature sequences proposed for deaminating deoxycytidines range between di-nucleotide to quad-nucleotide motifs8–11,16–21. A recent high-throughput assay suggested the preferred quad-nucleotide motif for A3A to be CTCG20. Although A3s are known to have varied sequence preference, quantitative and systematic studies of sequence specificity are incomplete. Recently, crystal structures of APOBEC3A (A3A) and APOBEC3B-CTD (an active site A3A chimera) with ssDNA have been solved20,22. However, despite these breakthrough structures, the molecular mechanism underlying substrate sequence specificity flanking the TC dinucleotide sequence remains unclear.