Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53-and-Nbs1-dependent manner
Resveratrol modulates DNA double-strand break repair pathways in an ATM/ATR-p53-and-Nbs1-dependent manner
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DOI：
10.1093/carcin/bgm283
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发表时间：
2008-03-01
期刊：
影响因子：
4.7
通讯作者：
Wiesmueller, Lisa
中科院分区：
文献类型：
--
作者：
Gatz, Susanne Andrea;Keimling, Marlen;Wiesmueller, Lisa
白藜芦醇（Resveratrol， RV）具有抑制肿瘤发生、促进和进展的作用，其作用机制主要与调控细胞周期和诱导细胞凋亡有关。到目前为止，关于其对基因组稳定性的影响，发表了模棱两可的观察结果。为了研究RV对DNA双链断裂（DSB）修复的影响，我们将建立的增强型绿色荧光蛋白（EGFP）和i - scei为基础的检测系统应用于RV处理的淋巴母细胞样细胞系（LCLs）。我们发现，RV独立于其已知的生长和死亡调节功能，抑制同源重组（HR）和非同源末端连接（NHEJ）。利用(i) p53状态不同的等基因细胞系TK6和WTK1， （ii）来自失调性毛细血管扩张患者的LCLs， （iii） shrna介导的p53敲低，（iv）咖啡因对ATM/ATR的化学抑制，我们建立了RV对HR抑制的ATM-p53依赖通路。来自奈亨断裂综合征患者的lcl的额外使用进一步提供了证据，证明RV治疗后，ATM/ atr - nbs1依赖于微同源性介导的NHEJ抑制。我们认为ATM和/或ATR的激活是RV的中心效应。对易出错重组亚通路的抑制至少可以部分解释这种天然植物成分在动物癌症模型中的化学预防作用。
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.