Genome-wide screens reveal that resveratrol induces replicative stress in human cells

Resveratrol is a natural product associated with wide-ranging effects in animal and cellular models including lifespan extension. To identify the genetic target of resveratrol in human cells, we conducted genome-wide CRISPR-Cas9 screens to pinpoint genes that confer sensitivity or resistance to resveratrol. An extensive network of DNA damage response and replicative stress genes exhibited genetic interactions with resveratrol and its analog pterostilbene. These genetic profiles showed similarity to the response to hydroxyurea, an inhibitor of ribonucleotide reductase that causes replicative stress. Resveratrol, pterostilbene and hydroxyurea caused similar depletion of nucleotide pools, inhibition of replication fork progression and induction of replicative stress. The ability of resveratrol to inhibit cell proliferation and S phase transit was independent of the histone deacetylase Sirtuin 1, which has been implicated in lifespan extension by resveratrol. These results establish that a primary impact of resveratrol on human cell proliferation is the induction of low-level replicative stress.白藜芦醇（Resveratrol）是一种天然产物，在动物与细胞模型中展现出广泛的生物学效应，其中包括寿命延长。为鉴定人类细胞中白藜芦醇的遗传靶点，我们开展了全基因组CRISPR-Cas9筛选，以精准定位赋予细胞对白藜芦醇敏感性或抗性的基因。一套涵盖大量DNA损伤应答与复制应激相关基因的广泛网络，与白藜芦醇及其类似物紫檀芪存在遗传互作。这些遗传特征与羟基脲（hydroxyurea）处理后的细胞响应高度相似——羟基脲是一种可引发复制应激的核糖核苷酸还原酶抑制剂。白藜芦醇、紫檀芪与羟基脲均可引发类似的核苷酸库耗竭、复制叉进程抑制以及复制应激诱导。白藜芦醇抑制细胞增殖与S期进程的能力，并不依赖于组蛋白去乙酰化酶沉默信息调节因子1（Sirtuin 1），该酶此前被认为参与了白藜芦醇介导的寿命延长效应。本研究结果证实，白藜芦醇对人类细胞增殖的主要影响是诱导低水平的复制应激。