Structural relationship of curcumin derivatives binding to the BRCT domain of human DNA polymerase λ

Abstract

We previously reported that phenolic compounds, petasiphenol and curcumin (diferuloylmethane), were a selective inhibitor of DNA polymerase λ (pol λ) in vitro. The purpose of this study was to investigate the molecular structural relationship of curcumin and 13 chemically synthesized derivatives of curcumin. The inhibitory effect on pol λ (full-length, i.e. intact pol λ including the BRCA1 C-terminal [BRCT] domain) by some derivatives was stronger than that by curcumin, and monoacetylcurcumin (compound 13) was the strongest pol λ inhibitor of all the compounds tested, achieving 50% inhibition at a concentration of 3.9 μM. The compound did not influence the activities of replicative pols such as α, δ and ε. It had no effect on pol β activity either, although the three-dimensional structure of pol β is thought to be highly similar to that of pol λ. Compound 13 did not inhibit the activity of the C-terminal catalytic domain of pol λ including the pol β-like core, in which the BRCT motif was deleted from its N-terminal region. MALDI-TOF MS analysis demonstrated that compound 13 bound selectively to the N-terminal domain of pol λ, but did not bind to the C-terminal region. Based on these results, the pol λ-inhibitory mechanism of compound 13 is discussed. © 2006 The Author(s) Journal compilation © 2006 by the Molecular Biology Society of Japan/Blackwell Publishing Ltd.