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.

白藜芦醇是一种天然产物，在动物和细胞模型中具有广泛的作用，包括延长寿命。为了鉴定白藜芦醇在人类细胞中的遗传靶标，我们进行了全基因组的CRISPR-Cas9筛选，以查明赋予白藜芦醇敏感性或抗性的基因。广泛的DNA损伤反应和复制性应激基因网络表现出与白藜芦醇及其类似物紫檀烯的遗传相互作用。这些遗传特征显示出与对羟基脲的反应相似，羟基脲是引起复制性应激的核糖核苷酸还原酶抑制剂。白藜芦醇，萜烯和羟基脲会导致类似的核苷酸池耗竭，抑制复制叉的进行以及诱导复制压力。白藜芦醇抑制细胞增殖和S期转运的能力与组蛋白脱乙酰基酶Sirtuin 1无关，后者已被白藜芦醇延长了寿命。这些结果证明白藜芦醇对人细胞增殖的主要影响是诱导低水平的复制应激。