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Published online 15 January 2004

Nucleic Acids Research, 2004, Vol. 32, No. 1 338-345
© 2004 Oxford University Press

Stereoselective excision of thymine glycol from oxidatively damaged DNA

Holly Miller*, Andrea S. Fernandes, Elena Zaika, Monica M. McTigue, M. Cecilia Torres1, Maryann Wente1, Charles R. Iden1 and Arthur P. Grollman

Laboratory of Chemical Biology and 1 Department of Pharmacological Sciences, State University of New York, Stony Brook, NY, USA

*To whom correspondence should be addressed. Tel: +1 631 444 6665; Fax: +1 631 444 7641; Email: miller{at}pharm.sunysb.edu

DNA damage created by reactive oxygen species includes the prototypic oxidized pyrimidine, thymine glycol (Tg), which exists in oxidatively damaged DNA as two diastereoisomeric pairs. In Escherichia coli, Saccharomyces cerevesiae and mice, Tg is preferentially excised by endonuclease III (Endo III) and endonuclease VIII (Endo VIII), yNTG1 and yNTG2, and mNTH and mNEIL1, respectively. We have explored the ability of these DNA glycosylases to discriminate between Tg stereoisomers. Oligonucleotides containing a single, chromatographically pure (5S,6R) or (5R,6S) stereoisomer of Tg were prepared by oxidation with osmium tetroxide. Steady-state kinetic analyses of the excision process revealed that Endo III, Endo VIII, yNTG1, mNTH and mNEIL1, but not yNTG2, excise Tg isomers from DNA in a stereoselective manner, as reflected in the parameter of catalytic efficiency (kcat/Km). When DNA glycosylases occur as complementary pairs, failure of one or both enzymes to excise their cognate Tg stereoisomer from oxidatively damaged DNA could have deleterious consequences for the cell.


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