Structural and biochemical impact of C8-aryl-guanine adducts within the Narl recognition DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity
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Date
2014
Authors
Sproviero, Michael
Verwey, Anne M. R.
Rankin, Katherine M.
Witham, Aaron A.
Soldatov, Dmitriy V.
Manderville, Richard A.
Fekry, Mostafa I.
Sturla, Shana J.
Sharma, Purshotam
Wetmore, Stacey D.
Journal Title
Journal ISSN
Volume Title
Publisher
Oxford University Press
Abstract
Chemical mutagens with an aromatic ring system
may be enzymatically transformed to afford aryl radical
species that preferentially react at the C8-site
of 2 -deoxyguanosine (dG). The resulting carbonlinked
C8-aryl-dG adduct possesses altered biophysical
and genetic coding properties compared to the
precursor nucleoside. Described herein are structural
and in vitro mutagenicity studies of a series of
fluorescent C8-aryl-dG analogues that differ in aryl
ring size and are representative of authentic DNA
adducts. These structural mimics have been inserted
into a hotspot sequence for frameshift mutations,
namely, the reiterated G3-position of the NarI sequence
within 12mer (NarI(12)) and 22mer (NarI(22))
oligonucleotides. In the NarI(12) duplexes, the C8-
aryl-dG adducts display a preference for adopting an
anti-conformation opposite C, despite the strong syn
preference of the free nucleoside. Using the NarI(22)
sequence as a template for DNA synthesis in vitro,
mutagenicity of the C8-aryl-dG adducts was assayed
with representative high-fidelity replicative versus
lesion bypass Y-family DNA polymerases, namely,
Escherichia coli pol I Klenow fragment exo− (Kf−)
and Sulfolobus solfataricus P2 DNA polymerase IV
(Dpo4). Our experiments provide a basis for a model
involving a two-base slippage and subsequent realignment
process to relate the miscoding properties of C-linked C8-aryl-dG adducts with their chemical
structures.
Description
Sherpa Romeo green journal, open access
Keywords
DNA , C8-aryl-dG adducts , NarI , Mutagenicity
Citation
Sproviero, M., Verwey, A. M. R., Rankin, K. M., Witham, A. A., Soldatov, D. V., Manderville, R. A. ... & Wetmore, S. D. (2014). Structural and biochemical impact of C8-aryl-guanine adducts within the NarI recognition of DNA sequence: influence of aryl ring size on targeted and semi-targeted mutagenicity. Nucleic Acids Research, 42(21), 13405-13421. doi:10.1093/nar/gku1093