Abasic site stabilization by aromatic DNA base surrogates: High-affinity binding to a baseflipping DNA-methyltransferase

Singh, I., Beuck, C., Bhattacharya, A. , Hecker, W., Parmar, V. S., Weinhold, E. and Seitz, O. (2004) Abasic site stabilization by aromatic DNA base surrogates: High-affinity binding to a baseflipping DNA-methyltransferase. Pure and Applied Chemistry, 76 (7-8). pp. 1563-1570. ISSN 0033-4545

Full content URL: http://dx.doi.org/10.1351/pac200476071563

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Item Type:Article
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DNA-methyltransferases catalyze the sequence-specific transfer of the methyl group of S-adenosylmethionine to target bases in genomic DNA. For gaining access to their target embedded within a double-helical structure, DNA-methyltransferases (DNA-MTases) rotate the target base out of the DNA helix. This base-flipping leads to the formation of an apparent abasic site. MTases such as cytosine-specific M(.)HhaI and M(.)HaeIII and also the repair enzyme uracil DNA glycosylase (UDG) insert amino acid side chains into the opened space and/or rearrange base-pairing. The adenine-specific DNA MTase M(.)TaqI binds without amino acid insertion. This binding mode allows for a substitution of the orphaned thymine with larger DNA base surrogates without steric interference by inserted amino acid side chains. DNA containing pyrenyl, naphthyl, acenaphthyl, and biphenyl residues was tested in M(.)TaqI binding studies. The synthesis of DNA building blocks required the formation of a C-glycosidic bond, which was established by using protected 1-chloro-2-deoxyribose as glycosyl donor and organocuprates as glycosyl acceptors. It is shown that all of the base surrogates enhanced the binding affinity to M(.)TaqI. Incorporation of pyrene increased the binding affinity by a factor of 400. Interestingly, there is a correlation between the observed order of dissociation constants and the ability of a base surrogate to stabilize abasic sites in model duplexes.

Additional Information:39th IUPAC Congress and 86th Conference of the Canadian Society for Chemistry: Chemistry at the Interfaces, Ottawa, Canada, 10–15 August 2003
Subjects:B Subjects allied to Medicine > B200 Pharmacology, Toxicology and Pharmacy
Divisions:College of Science > School of Pharmacy
ID Code:11305
Deposited On:24 Jul 2013 15:40

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