Inhibiting APOBEC3 Activity with Single-Stranded DNA
Containing 2′-Deoxyzebularine Analogues
Version 2 2019-01-24, 02:43
Version 1 2018-11-28, 18:23
Posted on 2019-01-24 - 02:43
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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Kvach, Maksim
V.; Barzak, Fareeda M.; Harjes, Stefan; Schares, Henry A. M.; Jameson, Geoffrey B.; Ayoub, Alex M.; et al. (2019). Inhibiting APOBEC3 Activity with Single-Stranded DNA
Containing 2′-Deoxyzebularine Analogues. ACS Publications. Collection. https://doi.org/10.1021/acs.biochem.8b00858
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AUTHORS (12)
MK
Maksim
V. Kvach
FB
Fareeda M. Barzak
SH
Stefan Harjes
HS
Henry A. M. Schares
GJ
Geoffrey B. Jameson
AA
Alex M. Ayoub
RM
Ramkumar Moorthy
HA
Hideki Aihara
RH
Reuben S. Harris
VF
Vyacheslav V. Filichev
DH
Daniel A. Harki
EH
Elena Harjes
KEYWORDS
APOBEC mutagenesismicromolar inhibition constantsanticancer therapiesAPOBEC 3A APOBEC 3Bdeaminating cytosineAPOBEC 3Gcancer cellsAPOBEC variantsacid-based inhibitorstitration calorimetrydZ-containing ssDNAsInhibiting APOBEC 3 Activitysubstrate-like APOBEC 3 inhibitorsresonance spectroscopy assaysincrease ratesAPOBEC 3 inhibitionsingle-stranded DNAfluorescence polarizationnanomolar dissociation constants