Journal
BIOCHEMISTRY
Volume 58, Issue 5, Pages 391-400Publisher
AMER CHEMICAL SOC
DOI: 10.1021/acs.biochem.8b00858
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Funding
- Worldwide Cancer Research [16-1197]
- Massey University Research Fund (MURF 2015) [7003]
- Institute of Fundamental Sciences of Massey University
- National Institutes of Health [R01-GM110129, R01-GM118000]
- University of Minnesota (UMN) Masonic Cancer Center (SPORE-Program Project planning seed grant)
- UMN College of Biological Sciences
- Prospect Creek Foundation
- Institute of Fundamental Sciences, Massey University
- UMN Office of the Vice President for Research
- Royal Society of New Zealand [IMF-Mau140]
- Massey University
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APOBEC3 enzymes form part of the innate immune system by deaminating cytosine to uracil in single-stranded DNA (ssDNA) and thereby preventing the spread of pathogenic genetic information. However, APOBEC mutagenesis is also exploited by viruses and cancer cells to increase rates of evolution, escape adaptive immune responses, and resist drugs. This raises the possibility of APOBEC3 inhibition as a strategy for augmenting existing antiviral and anticancer therapies. Here we show that, upon incorporation into short ssDNAs, the cytidine nucleoside analogue 2'-deoxyzebularine (dZ) becomes capable of inhibiting the catalytic activity of selected APOBEC variants derived from APOBEC3A, APOBEC3B, and APOBEC3G, supporting a mechanism in which ssDNA delivers dZ to the active site. Multiple experimental approaches, including isothermal titration calorimetry, fluorescence polarization, protein thermal shift, and nuclear magnetic resonance spectroscopy assays, demonstrate nanomolar dissociation constants and low micromolar inhibition constants. These dZ-containing ssDNAs constitute the first substrate-like APOBEC3 inhibitors and, together, comprise a platform for developing nucleic acid-based inhibitors with cellular activity.
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