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Insights into the molecular mechanism of alkylation‐induced mutagenesis
Author(s) -
Lee Seongmin
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.647.5
Subject(s) - mutagenesis , thymine , dna , dna damage , base pair , molecular structure of nucleic acids: a structure for deoxyribose nucleic acid , cisplatin , chemistry , dna repair , dna polymerase , biochemistry , nucleobase , mutation , stereochemistry , biology , genetics , gene , chemotherapy
The genomic DNA is persistently attacked by endogenous and exogenous alkylating agents (e.g., S‐adenosyl methionine, cisplatin), which gives rise to a wide variety of alkylated DNA lesions such as N7‐MeG, N3‐MeA, O6‐MeG, and cisplatin‐GG intrastrand cross‐links. These lesions, if not removed by DNA repair pathways, can be bypassed by error‐prone translesion synthesis DNA polymerases, which could cause mutations and cancers. The structural basis for promutagenic replication past these lesions remains elusive. To elucidate the alkylation‐induced mutagenesis mechanism, we conducted kinetic and structural studies of the bypass of these lesions by various human DNA polymerases. N7‐MeG formed a Watson‐Crick‐like base pair, rather than a wobble base pair, with thymine, suggesting promutagenicity of N7‐MeG. N3‐MeA formed a Watson‐Crick base pair with thymine but strongly deterred nucleotide incorporation opposite the lesion. O6‐MeG formed a Watson‐Crick‐like base pair with thymine, which was consistent with the reported high mutagenicity and carcinogenicity of O6‐MeG. Cisplatin‐GG intrastrand cross‐links engage in favorable interactions with adenine in non‐instructional fashion, suggesting that the predominant cisplatin‐induced G to T mutations may follow an “A‐rule”. Taken together, these studies revealed the features of promutagenic base pairings of N7‐MeG, O6‐MeG and cisplatin‐GG cross‐links, thereby providing new insights into the molecular mechanisms of alkylated‐induced mutagenesis and carcinogenesis. Support or Funding Information Welch Foundation F‐1741 National Institutes of Health ES26676 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .