APOBEC-1 cofactors regulate APOBEC3-induced mutations in hepatitis B virus

As human host restriction factors, A3s play an important role against viral infections. A3s are also major mutagenic drivers of cancer. However, why A3-induced mutations vary significantly from non-lethal mutations in virus to localized hypermutations in cancer remains unknown. We found that A1 cofactor and other hnRNPs are not only associated with A3 complexes but also play important regulatory roles in A3-induced mutation activities. A1 cofactors like GRY-RBP significantly increased A3 accessibility and mutational efficiency to its single-strand DNA substrate during HBV reverse transcription to generate hypermutations. Disruption of the A3 protein association with hnRNPs by A3 mutagenesis diminished A3 mutational activity. This finding not only reveals a regulatory mechanism for A3-induced mutation but also indicates that A3-associated cellular factors can be a potential target for regulating A3-induced mutation for cancer therapeutics.