Nucleic Acids Research, Vol 25, Issue 16 3354-3361, Copyright © 1997 by Oxford University Press
TE Spratt and DE Levy
During DNA replication, mutations occur when an incorrect dNTP is
incorporated opposite a carcinogen-modified nucleotide. We have probed the
structures of the interaction between O 6-methylguanine ( O 6mG) and
cytosine and thymine during replication by kinetic means in order to
examine the structure during the rate determining step. The kinetics of
incorporation of dCTP and dTTP opposite O 6mG and three analogs, S 6-
methyl-6-thioguanine, O 6-methyl-1-deazaguanine and O 6-
methylhypoxanthine, have been measured with four polymerases, the Klenow
fragment of DNA polymerase I, the Klenow fragment with the proof- reading
exonuclease inactivated, Taq and Tth polymerases. In the insertion of dTTP
opposite O 6mG, a large decrease in V max/ K m was observed only upon
modification of the N1 position. This result is consistent with a
Watson-Crick type configuration. For the incorporation of dCTP, the V max/
K m was significantly decreased only with removal of the exocyclic amino
group at the 2 position. The pH dependence of the ratio of incorporation of
dCTP and dTTP was independent of pH at physiological pH. This result
suggests that dCTP is incorporated via an uncharged complex such as the
wobble configuration.
ARTICLES
Structure of the hydrogen bonding complex of O6-methylguanine with cytosine and thymine during DNA replication
American Health Foundation, Division of Pathology and Toxicology, 1 Dana Road, Valhalla, NY 10595, USA. tomspratt@aol.com
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