A prevalent cancer susceptibility APOBEC3A hybrid allele bearing APOBEC3B 3′UTR enhances chromosomal DNA damage

Human APOBEC3A (A3A) cytidine deaminase is a host enzyme that can introduce mutations into chromosomal DNA. As APOBEC3B (A3B) encodes a C-terminal catalytic domain ~91% identical to A3A, we examined its genotoxic potential as well as that of a highly prevalent chimaeric A3A–A3B deletion allele (ΔA3B), which is linked to a higher odds ratio of developing breast, ovarian and liver cancer. Interestingly, breast cancer genomes from ΔA3B−/− patients show a higher overall mutation burden. Here it is shown that germline A3B can hypermutate nuclear DNA, albeit less efficiently than A3A. Chimaeric A3A mRNA resulting from ΔA3B was more stable, resulting in higher intracellular A3A levels and greater DNA damage. The cancer burden implied by the higher A3A levels could be considerable given the high penetration of the ΔA3B allele in South East Asia.