title: Structures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations.
abstract: N-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.
authors.affiliation: Graduate School of Science and Engineering, Iwaki-Meisei University, Iwaki 970-8551, Japan.
authors.forename: Fang
authors.initials: F
authors.lastname: Zhang
authors.forename: Masaru
authors.initials: M
authors.lastname: Tsunoda
authors.forename: Kaoru
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yuji
authors.initials: Y
authors.lastname: Kikuchi
authors.forename: Oliver
authors.initials: O
authors.lastname: Wilkinson
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Millington
authors.forename: Geoffrey P
authors.initials: GP
authors.lastname: Margison
authors.forename: David M
authors.initials: DM
authors.lastname: Williams
authors.forename: Ella
authors.initials: E
authors.lastname: Czarina Morishita
authors.forename: Akio
authors.initials: A
authors.lastname: Takénaka
mesh_terms: D020029:Base Pairing; D003562:Cytidine / Q000737:chemistry; D004247:DNA / Q000737:chemistry*; D004259:DNA-Directed DNA Polymerase / Q000737:chemistry; D006151:Guanosine / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D008958:Models, Molecular; D009154:Mutation; D013941:Thymine / Q000737:chemistry; D000099270:Y-Family DNA Polymerases
chemical_list: D003562:Cytidine; D004247:DNA; D004259:DNA-Directed DNA Polymerase; D006151:Guanosine; D013941:Thymine; C112338:Rad30 protein; D000099270:Y-Family DNA Polymerases