AID, APOBEC3A and APOBEC3B efficiently deaminate deoxycytidines neighboring DNA damage induced by oxidation or alkylation

Abstract

AID/APOBEC3s are endogenous enzymes that deaminate deoxycytidine (dC) to deoxyuridine (dU). Although they can mutate any dC, each family member has a unique sequence preference determined by nucleotides immediately surrounding the target dC. This WRC (W=A/T, R=A/G) and YC (Y=T/C) preference is well established for AID and APOBEC3A/B respectively. Common sources of DNA damage such as alkylation and oxidation alter the chemistry of normal base side chains prompting us to examine the activity of AID, APOBEC3A, and APOBEC3B on dCs whose neighboring -2 or -1 position bases are damaged through oxidation or alkylation. We found that all three enzymes efficiently deaminate dC when common damaged bases are present in the -2 and -1 positions. Strikingly, some of these motifs supported even higher catalytic efficiencies by AID, APOBEC3A and APOBEC3B compared to WRC/YC motifs which are their most favored normal DNA sequences. Based on interactions of the surfaces of AID, APOBEC3A and APOBEC3B with DNA as resolved by structural studies, we then modeled interactions with alkylated or oxidized bases. Corroborating the enzyme kinetics experiments, these analyses suggest that the surface regions responsible for recognition of normal bases can also interact with oxidized and alkylated bases. Thus, our data extend the current knowledge of the -2 and -1 position substrate sequence specificity of AID/A3s to include common damaged base motifs.