Zhang, F, Tsunoda, M, Suzuki, K et al. (7 more authors) (2013) Structures of DNA duplexes containing O-6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations. Nucleic Acids Research, 41 (10). 5524 - 5532. ISSN 0305-1048
Abstract
N-nitrosation of glycine and its derivatives generates potent alkylating agents that can lead to the formation of O6-carboxymethylguanine (O6-CMG) in DNA. O6-CMG has been identified in DNA derived from human colon tissue, and its occurrence has been linked to diets high in red and processed meats. By analogy to O6-methylguanine, O6-CMG is expected to be highly mutagenic, inducing G to A mutations during DNA replication that can increase the risk of gastrointestinal and other cancers. Two crystal structures of DNA dodecamers d(CGCG[O6-CMG]ATTCGCG) and d(CGC[O6-CMG]A ATTCGCG) in complex with Hoechst33258 reveal that each can form a self-complementary duplex to retain the B-form conformation. Electron density maps clearly show that O6-CMG forms a Watson– Crick–type pair with thymine similar to the canonical A:T pair, and it forms a reversed wobble pair with cytosine. In situ structural modeling suggests that a DNA polymerase can accept the Watson–Crick–type pair of O6-CMG with thymine, but might also accept the reversed wobble pair of O6-CMG with cytosine. Thus, O6-CMG would permit the mis-incorporation of dTTP during DNA replication. Alternatively, the triphosphate that would be formed by carboxymethylation of the nucleotide triphosphate pool d[O6-CMG]TP might compete with dATP incorporation opposite thymine in a DNA template.
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Copyright, Publisher and Additional Information: | © 2013 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Licence (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. | ||||
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Institution: | The University of Sheffield | ||||
Academic Units: | The University of Sheffield > Faculty of Science (Sheffield) > Department of Chemistry (Sheffield) | ||||
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Depositing User: | Symplectic Sheffield | ||||
Date Deposited: | 07 May 2014 14:58 | ||||
Last Modified: | 07 May 2014 14:58 | ||||
Published Version: | http://dx.doi.org/10.1093/nar/gkt198 | ||||
Status: | Published | ||||
Publisher: | Oxford University Press | ||||
Refereed: | Yes | ||||
Identification Number: | https://doi.org/10.1093/nar/gkt198 |