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dc.contributor.authorZhang, F
dc.contributor.authorTsunoda, M
dc.contributor.authorSuzuki, K
dc.contributor.authorKikuchi, Y
dc.contributor.authorWilkinson, O
dc.contributor.authorMillington, C
dc.contributor.authorMargison, Geoffrey P
dc.contributor.authorWilliams, D
dc.contributor.authorCzarina M
dc.contributor.authorTakénaka, A
dc.date.accessioned2013-05-20T12:44:19Z
dc.date.available2013-05-20T12:44:19Z
dc.date.issued2013-04-10
dc.identifier.citationStructures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations. 2013: Nucleic Acids Resen_GB
dc.identifier.issn1362-4962
dc.identifier.pmid23580550
dc.identifier.doi10.1093/nar/gkt198
dc.identifier.urihttp://hdl.handle.net/10541/292374
dc.description.abstractN-nitrosation of glycine and its derivatives generates potent alkylating agents that can lead to the formation of O(6)-carboxymethylguanine (O(6)-CMG) in DNA. O(6)-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 O(6)-methylguanine, O(6)-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[O(6)-CMG]ATTCGCG) and d(CGC[O(6)-CMG]AATTCGCG) 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 O(6)-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 O(6)-CMG with thymine, but might also accept the reversed wobble pair of O(6)-CMG with cytosine. Thus, O(6)-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[O(6)-CMG]TP might compete with dATP incorporation opposite thymine in a DNA template.
dc.languageENG
dc.language.isoenen
dc.rightsArchived with thanks to Nucleic acids researchen_GB
dc.titleStructures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations.en
dc.typeArticleen
dc.contributor.departmentGraduate School of Science and Engineering, Iwaki-Meisei University, Iwaki 970-8551, Japan, Faculty of Pharmacy, Iwaki-Meisei University, Iwaki 970-8551, Japan, Department of Chemistry, Centre for Chemical Biology, Krebs Institute, University of Sheffield, Sheffield S3 7HF, UK, Cancer Research-UK Carcinogenesis Group, Paterson Institute for Cancer Research, University of Manchester, Manchester M20 9BX, UK and Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama 226-8501, Japan.en_GB
dc.identifier.journalNucleic Acids Researchen_GB
html.description.abstractN-nitrosation of glycine and its derivatives generates potent alkylating agents that can lead to the formation of O(6)-carboxymethylguanine (O(6)-CMG) in DNA. O(6)-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 O(6)-methylguanine, O(6)-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[O(6)-CMG]ATTCGCG) and d(CGC[O(6)-CMG]AATTCGCG) 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 O(6)-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 O(6)-CMG with thymine, but might also accept the reversed wobble pair of O(6)-CMG with cytosine. Thus, O(6)-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[O(6)-CMG]TP might compete with dATP incorporation opposite thymine in a DNA template.


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