Petasiphenol: A DNA Polymerase λ Inhibitor

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Abstract
Petasiphenol, a bio-antimutagen isolated from a Japanese vegetable, Petasites japonicus, selectively inhibits the activities of mammalian DNA polymerase λ (pol λ) in vitro. The compound did not influence the activities of replicative DNA polymerases such as α, δ, and ε but also showed no effect even on the pol β activity, the three-dimensional structure of which is thought to be highly similar to pol λ. The inhibitory effect of petasiphenol on intact pol λ including the BRCA1 C-terminus (BRCT) domain was dose-dependent, and 50% inhibition was observed at a concentration of 7.8 μM. The petasiphenol-induced inhibition of the pol λ activity was noncompetitive with respect to both the DNA template-primer and the dNTP substrate. Petasiphenol did not only inhibit the activity of the truncated pol λ including the pol β-like core, in which the BRCT motif was deleted in its N-terminal region. BIAcore analysis demonstrated that petasiphenol bound selectively to the N-terminal domain of pol λ but did not bind to the C-terminal region. On the basis of these results, the pol λ inhibitory mechanism of petasiphenol is discussed.