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J. Biol. Chem., Vol. 276, Issue 22, 18999-19005, June 1, 2001
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on Templates with Platinum-DNA
Adducts*
,
From the Department of Biochemistry and Biophysics, Lineberger
Comprehensive Cancer Center, School of Medicine, University of North
Carolina, Chapel Hill, North Carolina 27599-7260
DNA adducts formed by platinum-based anticancer
drugs interfere with DNA replication. The carrier ligand of the
platinum compound is likely to affect the conformation of the Pt-DNA
adducts. In addition, the conformation of the adduct can also change
upon binding of damaged DNA to the active site of DNA polymerase. From the crystal structures of pol 
ternary complexes it is
evident that undamaged gapped and primed single-stranded (non-gapped) DNA templates exist in very different conformations when bound to pol
. Therefore, one might expect that the constraints imposed on the
damaged templates by binding to the polymerase active site should also
affect the conformation of the Pt-DNA adducts and their ability to
inhibit DNA replication. In support of this hypothesis we have found
that the efficiency, carrier ligand specificity, site of discrimination
(3'-G versus 5'-G of the Pt-GG adducts), and fidelity of
translesion synthesis past Pt-DNA adducts by pol are strongly
affected by the structure of the DNA template. Previous studies have
suggested that the conformation of Pt-DNA adducts may be affected by
the sequence context of the adduct. In support of this
hypothesis, our data show that sequence context affects the efficiency,
fidelity, and pattern of misincorporation by pol .
Present address: Section on DNA Replication, Repair, and
Mutagenesis, NICHD, National Institutes of Health, Bethesda, MD
20892-2725.
§
To whom correspondence should be addressed. Tel.: 919-966-3286;
Fax: 919-966-2852; E-mail: Stephen_Chaney@med.unc.edu.
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