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Nucleic Acids Research, 2001, Vol. 29, No. 16 3433-3438
© 2001 Oxford University Press

Methylglyoxal, an endogenous aldehyde, crosslinks DNA polymerase and the substrate DNA

Naoko Murata-Kamiya and Hiroyuki Kamiya1,*

Institute of Industrial Ecological Sciences, University of Occupational and Environmental Health, 1-1 Iseigaoka, Yahatanishi-ku, Kitakyushu 807-8555, Japan and 1Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-12, Nishi-6, Kita-ku, Sapporo 060-0812, Japan

Methylglyoxal, a known endogenous and environmental mutagen, is a reactive {alpha}-ketoaldehyde that can modify both DNA and proteins. To investigate the possibility that methylglyoxal induces a crosslink between DNA and DNA polymerase, we treated a ‘primed template’ DNA and the exonuclease-deficient Klenow fragment (KFexo–) of DNA polymerase I with methylglyoxal in vitro. When the reaction mixtures were analyzed by SDS–PAGE, we found that methylglyoxal induced a DNA–KFexo– crosslink. The specific binding complex of KFexo– and ‘primed template’ DNA was necessary for formation of the DNA–KFexo– crosslink. Methylglyoxal reacted with guanine residues in the single-stranded portion of the template DNA. When 2'-deoxyguanosine was incubated with N{alpha}-acetyllysine or N-acetylcysteine in the presence of methylglyoxal, a crosslinked product was formed. No other amino acid derivatives tested could generate a crosslinked product. These results suggest that methylglyoxal crosslinks a guanine residue of the substrate DNA and lysine and cysteine residues near the binding site of the DNA polymerase during DNA synthesis and that DNA replication is severely inhibited by the methylglyoxal-induced DNA–DNA polymerase crosslink.

* To whom correspondence should be addressed. Tel: +81 11 706 3733; Fax: +81 11 706 4879; Email: hirokam{at}pharm.hokudai.ac.jp Present address:Naoko Murata-Kamiya, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai 980-8578, Japan and CREST, Japan Science and Technology, Japan


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