Molecular Cell
Volume 79, Issue 5, 3 September 2020, Pages 846-856.e8
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Short Article
Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells

https://doi.org/10.1016/j.molcel.2020.07.010Get rights and content
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Highlights

  • CRISPR screens reveal a shared genetic profile between hydroxyurea and resveratrol

  • Resveratrol or hydroxyurea led to replicative stress and delayed S phase transit

  • The impact of resveratrol on proliferation or S phase was independent of SIRT1

Summary

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.

Keywords

resveratrol
hydroxyurea
CRISPR-Cas9
genome-wide screen
human cells
SIRT1
replicative stress
nucleotide pools
DNA replication
cell proliferation

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These authors contributed equally

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