Interaction between DNA Polymerase lambda and anticancer nucleoside analogs.

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Garcia-Diaz M, Murray MS, Kunkel TA, Chou KM

Interaction between DNA Polymerase lambda and anticancer nucleoside analogs.

J Biol Chem. 2010 May 28;285(22):16874-9. doi: 10.1074/jbc.M109.094391. Epub 2010 Mar 26.

PubMed ID

20348107 [ View in PubMed

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Abstract

The anticancer activity of cytarabine (AraC) and gemcitabine (dFdC) is thought to result from chain termination after incorporation into DNA. To investigate their incorporation into DNA at atomic level resolution, we present crystal structures of human DNA polymerase lambda (Pol lambda) bound to gapped DNA and containing either AraC or dFdC paired opposite template dG. These structures reveal that AraC and dFdC can bind within the nascent base pair binding pocket of Pol lambda. Although the conformation of the ribose of AraCTP is similar to that of normal dCTP, the conformation of dFdCTP is significantly different. Consistent with these structures, Pol lambda efficiently incorporates AraCTP but not dFdCTP. The data are consistent with the possibility that Pol lambda could modulate the cytotoxic effect of AraC.

DrugBank Data that Cites this Article

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Gemcitabine	DNA	Nucleotide	Humans	Yes	Cross-linking/alkylation	Details