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Genes to Cells (2006) 11, 223-235. doi:10.1111/j.1365-2443.2006.00937.x
© 2006 Blackwell Publishing or its licensors
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Structural relationship of curcumin derivatives binding to the BRCT domain of human DNA polymerase {lambda}

Toshifumi Takeuchi1, Tomomi Ishidoh2, Hiroshi Iijima2, Isoko Kuriyama2, Noriko Shimazaki1, Osamu Koiwai1, Kouji Kuramochi1, Susumu Kobayashi3,4, Fumio Sugawara1,4, Kengo Sakaguchi1,4, Hiromi Yoshida2,5 and Yoshiyuki Mizushina2,5,*

1 Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan
2 Department of Nutritional Science, Kobe-Gakuin University, Kobe, Hyogo, Japan
3 Faculty of Pharmaceutical Sciences, Tokyo University of Science, Noda, Chiba, Japan
4 Frontier Research Center for Genome and Drug Discovery, Tokyo University of Science, Noda, Chiba, Japan
5 High Technology Research Center, Kobe-Gakuin University, Kobe, Hyogo, Japan

We previously reported that phenolic compounds, petasiphenol and curcumin (diferuloylmethane), were a selective inhibitor of DNA polymerase {lambda} (pol {lambda}) 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 {lambda} (full-length, i.e. intact pol {lambda} including the BRCA1 C- terminal [BRCT] domain) by some derivatives was stronger than that by curcumin, and monoacetylcurcumin (compound 13) was the strongest pol {lambda} 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 {alpha}, {delta}, and {varepsilon}. It had no effect on pol ß activity either, although the three-dimensional structure of pol ß is thought to be highly similar to that of pol {lambda}. Compound 13 did not inhibit the activity of the C-terminal catalytic domain of pol {lambda} including the pol ß-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 {lambda}, but did not bind to the C-terminal region. Based on these results, the pol {lambda}-inhibitory mechanism of compound 13 is discussed.

Communicated by: Fumio Hanaoka

* Correspondence: E-mail: mizushin{at}nutr.kobegakuin.ac.jp






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