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Nucleic Acids Research, 2003, Vol. 31, No. 19 5501-5512
© 2003 Oxford University Press

Vanillins—a novel family of DNA-PK inhibitors

Stephen Durant* and Peter Karran

Mammalian DNA Repair, Cancer Research UK, London Research Institute, Clare Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Herts, EN6 3LD, UK

*To whom correspondence should be addressed. Tel: +44 207 2693882; Fax: +44 207 2693801; Email: s.durant{at}cancer.org.uk

Non-homologous DNA end-joining (NHEJ) is a major pathway of double strand break (DSB) repair in human cells. Here we show that vanillin (3-methoxy-4-hydroxybenzaldehyde)—a naturally occurring food component and an acknowledged antimutagen, anticlastogen and anticarcinogen—is an inhibitor of NHEJ. Vanillin blocked DNA end-joining by human cell extracts by directly inhibiting the activity of DNA-PK, a crucial NHEJ component. Inhibition was selective and vanillin had no detectable effect on other steps of the NHEJ process, on an unrelated protein kinase or on DNA mismatch repair by cell extracts. Subtoxic concentrations of vanillin did not affect the ATM/ATR-dependent phosphorylation of Chk2 or the S-phase checkpoint response after ionising radiation. They significantly potentiated the cytotoxicity of cisplatin, but did not affect sensitivity to UVC. A limited screen of structurally related compounds identified two substituted vanillin derivatives that were 100- and 50-fold more potent than vanillin as DNA-PK inhibitors. These compounds also sensitised cells to cisplatin. The inhibition of NHEJ is consistent with the antimutagenic and other biological properties of vanillin, possibly altering the balance between DSB repair by NHEJ and homologous recombination.


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