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.

journal_name

Nucleic Acids Res

journal_title

Nucleic acids research

authors

Zhang F,Tsunoda M,Suzuki K,Kikuchi Y,Wilkinson O,Millington CL,Margison GP,Williams DM,Czarina Morishita E,Takénaka A

doi

10.1093/nar/gkt198

subject

Has Abstract

pub_date

2013-05-01 00:00:00

pages

5524-32

issue

10

eissn

0305-1048

issn

1362-4962

pii

gkt198

journal_volume

41

pub_type

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