Journal Article

Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR–p53- and –Nbs1-dependent manner

Susanne Andrea Gatz, Marlen Keimling, Cindy Baumann, Thilo Dörk, Klaus-Michael Debatin, Simone Fulda and Lisa Wiesmüller

in Carcinogenesis

Volume 29, issue 3, pages 519-527
Published in print March 2008 | ISSN: 0143-3334
Published online January 2008 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm283
Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR–p53- and –Nbs1-dependent manner

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Resveratrol (RV) inhibits tumour initiation, promotion and progression which has mainly been explained by its properties in cell cycle control and apoptosis induction. So far, ambiguous observations have been published regarding its influence on genomic stability. To study RV's effects on DNA double-strand break (DSB) repair, we applied the established enhanced green fluorescent protein (EGFP)- and I-SceI-based assay system on RV-treated lymphoblastoid cell lines (LCLs). We show that RV inhibits both, homologous recombination (HR) and non-homologous end joining (NHEJ) independently of its known growth and death regulatory functions. Using (i) the isogenic cell lines TK6 and WTK1, which differ in their p53 status, (ii) LCLs from patients with ataxia telangiectasia, (iii) shRNA-mediated p53 knockdown and (iv) chemical inhibition of ATM/ATR by caffeine, we established an ATM–p53-dependent pathway of HR inhibition by RV. Additional use of LCLs from Nijmegen breakage syndrome patients furthermore provided evidence for an ATM/ATR–Nbs1-dependent inhibition of microhomology-mediated NHEJ after RV treatment. We propose that activation of ATM and/or ATR is a central effect of RV. Repression of error-prone recombination subpathways could at least partially explain the chemopreventive effects of this natural plant constituent in animal cancer models.

Journal Article.  7174 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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