Human DNA cytosine-to-uracil deaminases catalyze mutations in both pathogen and cellular genomes. APOBEC3D, APOBEC3F, APOBEC3G, and APOBEC3H restrict human immunodeficiency virus 1 (HIV-1) infection in cells deficient in the viral infectivity factor (Vif), and have the potential to catalyze sublethal levels of mutation in viral genomes in Vif-proficient cells. At least two APOBEC3 enzymes, and in particular APOBEC3B, are sources of somatic mutagenesis in cancer cells that drive tumor evolution and may manifest clinically as recurrence, metastasis, and/or therapy resistance. Consequently, APOBEC3 enzymes are tantalizing targets for developing chemical probes and therapeutic molecules to harness mutational processes in human disease. This review highlights recent efforts to chemically manipulate APOBEC3 activities. APOBECs are single-stranded DNA cytosine-to-uracil deaminases that perform essential roles in innate immunity by restricting foreign DNA; however, their aberrant activities can drive mutagenesis of virus and cancer genomes. Here, Olson et al. review chemical approaches to harness APOBEC mutagenesis as a new strategy to control genome evolution in human disease.
Bibliographical noteFunding Information:
We apologize to colleagues whose work could not be cited due to space constraints. This work was supported by NIH grants R01-GM110129 and R01-GM118000 to D.A.H. and R.S.H., R37-AI064046 and R21-CA206309 to R.S.H., and F31-CA183246 to M.E.O. The authors thank Dr. Nadine Shaban for assistance with Figure 5 A. R.S.H. is the Margaret Harvey Schering Land Grant Chair for Cancer Research, a Distinguished McKnight University Professor, and an Investigator of the Howard Hughes Medical Institute. D.A.H. and R.S.H. are co-founders, shareholders, and consultants of ApoGen Biotechnologies.
- chemical probes