4ITD

Structures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing transition mutation

Summary for 4ITD

• Entry DOI: 10.2210/pdb4itd/pdb
• Related: 4IJ0
• Descriptor: DNA (5'-D(*CP*GP*CP*GP*(C6G)P*AP*TP*TP*CP*GP*CP*G)-3'), MAGNESIUM ION, 2'-(4-HYDROXYPHENYL)-5-(4-METHYL-1-PIPERAZINYL)-2,5'-BI-BENZIMIDAZOLE, ... (4 entities in total)
• Functional Keywords: damaged dna, o6-carboxymethylguanine, mutagenesis, dna
• Total number of polymer chains: 2
• Total formula weight: 7923.66

Authors

Zhang, F.,Suzuki, K.,Tsunoda, M.,Wilkinson, O.,Millington, C.L.,Williams, D.M.,Morishita, E.C.,Takenaka, A. (deposition date: 2013-01-18, release date: 2013-05-08, Last modification date: 2024-03-20)

Primary citation

Zhang, F.,Tsunoda, M.,Suzuki, K.,Kikuchi, Y.,Wilkinson, O.,Millington, C.L.,Margison, G.P.,Williams, D.M.,Czarina Morishita, E.,Takenaka, A.
Structures of DNA duplexes containing O6-carboxymethylguanine, a lesion associated with gastrointestinal cancer, reveal a mechanism for inducing pyrimidine transition mutations
Nucleic Acids Res., 41:5524-5532, 2013

PubMed 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.

PubMed: 23580550
DOI: 10.1093/nar/gkt198

Experimental method

X-RAY DIFFRACTION (1.94 Å)