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The use of an artificial nucleotide for polymerase-based recognition of carcinogenic O<sup>6</sup>-alkylguanine DNA adducts

The use of an artificial nucleotide for polymerase-based recognition of carcinogenic O6-alkylguanine DNA adducts

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WYSS, Laura A., Arman NILFOROUSHAN, David M. WILLIAMS, Andreas MARX, Shana J. STURLA, 2016. The use of an artificial nucleotide for polymerase-based recognition of carcinogenic O6-alkylguanine DNA adducts. In: Nucleic Acids Research. 44(14), pp. 6564-6573. ISSN 0301-5610. eISSN 1362-4962. Available under: doi: 10.1093/nar/gkw589

@article{Wyss2016artif-37294, title={The use of an artificial nucleotide for polymerase-based recognition of carcinogenic O6-alkylguanine DNA adducts}, year={2016}, doi={10.1093/nar/gkw589}, number={14}, volume={44}, issn={0301-5610}, journal={Nucleic Acids Research}, pages={6564--6573}, author={Wyss, Laura A. and Nilforoushan, Arman and Williams, David M. and Marx, Andreas and Sturla, Shana J.} }

Nilforoushan, Arman Marx, Andreas Sturla, Shana J. Wyss, Laura A. The use of an artificial nucleotide for polymerase-based recognition of carcinogenic O<sup>6</sup>-alkylguanine DNA adducts Enzymatic approaches for locating alkylation adducts at single-base resolution in DNA could enable new technologies for understanding carcinogenesis and supporting personalized chemotherapy. Artificial nucleotides that specifically pair with alkylated bases offer a possible strategy for recognition and amplification of adducted DNA, and adduct-templated incorporation of an artificial nucleotide has been demonstrated for a model DNA adduct O<sup>6</sup>-benzylguanine by a DNA polymerase. In this study, DNA adducts of biological relevance, O<sup>6</sup>-methylguanine (O<sup>6</sup>-MeG) and O<sup>6</sup>-carboxymethylguanine (O<sup>6</sup>-CMG), were characterized to be effective templates for the incorporation of benzimidazole-derived 2'-deoxynucleoside-5'-O-triphosphates ( BENZI: TP and BIM: TP) by an engineered KlenTaq DNA polymerase. The enzyme catalyzed specific incorporation of the artificial nucleotide BENZI: opposite adducts, with up to 150-fold higher catalytic efficiency for O<sup>6</sup>-MeG over guanine in the template. Furthermore, addition of artificial nucleotide BENZI: was required for full-length DNA synthesis during bypass of O<sup>6</sup>-CMG. Selective incorporation of the artificial nucleotide opposite an O<sup>6</sup>-alkylguanine DNA adduct was verified using a novel 2',3'-dideoxy derivative of BENZI: TP. The strategy was used to recognize adducts in the presence of excess unmodified DNA. The specific processing of BENZI: TP opposite biologically relevant O<sup>6</sup>-alkylguanine adducts is characterized herein as a basis for potential future DNA adduct sequencing technologies. eng 2017-02-10T08:17:11Z Marx, Andreas 2017-02-10T08:17:11Z Wyss, Laura A. Williams, David M. Williams, David M. Nilforoushan, Arman Sturla, Shana J. 2016

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