Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53- and -Nbs1-dependent manner.
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.
Gatz
Susanne Andrea
SA
Children's Hospital of the University of Ulm, Eythstrasse 24, D-89075 Ulm, Germany. susanne.gatz@uniklinik-ulm.de
Keimling
Marlen
M
Baumann
Cindy
C
Dörk
Thilo
T
Debatin
Klaus-Michael
KM
Fulda
Simone
S
Wiesmüller
Lisa
L
D017209:Apoptosis; D064007:Ataxia Telangiectasia Mutated Proteins; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000502:physiology*; D002460:Cell Line; D004249:DNA Damage; D004260:DNA Repair; D004268:DNA-Binding Proteins / Q000502:physiology*; D006801:Humans; D009687:Nuclear Proteins / Q000502:physiology*; D017346:Protein Serine-Threonine Kinases / Q000502:physiology*; D011995:Recombination, Genetic; D000077185:Resveratrol; D013267:Stilbenes / Q000494:pharmacology*; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000502:physiology*
D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D013267:Stilbenes; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; C576597:ATR protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases; D000077185:Resveratrol