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Genome-Wide Screens Reveal that Resveratrol Induces Replicative Stress in Human Cells

Yahya Benslimane1, Thierry Bertomeu1, Jasmin Coulombe-Huntington1

  • 1Institute for Research in Immunology and Cancer, Université de Montréal, PO Box 6128, Downtown Station, Montréal, QC H3C 3J7, Canada.

Molecular Cell
|August 7, 2020
PubMed

Insights

Resveratrol and pterostilbene induce replicative stress in human cells by depleting nucleotide pools, impacting cell proliferation independently of sirtuin 1. This reveals a key mechanism of action for these natural compounds.

Area of Science:

  • Molecular Biology
  • Genetics
  • Cell Biology

Background:

  • Resveratrol is a natural compound with documented effects on lifespan in various models.
  • Its precise genetic targets in human cells remain incompletely understood.

Purpose of the Study:

  • To identify the genetic targets of resveratrol in human cells using genome-wide CRISPR-Cas9 screening.
  • To elucidate the mechanism by which resveratrol affects cell proliferation.

Main Methods:

  • Genome-wide CRISPR-Cas9 screens were employed to identify genes conferring sensitivity or resistance to resveratrol.
  • Comparative analysis of genetic interactions and cellular responses to resveratrol, pterostilbene, and hydroxyurea.

Main Results:

  • A network of DNA damage response and replicative stress genes showed genetic interactions with resveratrol and pterostilbene.
  • Resveratrol, pterostilbene, and hydroxyurea induced similar nucleotide pool depletion, inhibited replication, and caused replicative stress.
  • Resveratrol's inhibition of cell proliferation and S phase transit was independent of sirtuin 1.

Conclusions:

  • Resveratrol's primary impact on human cell proliferation is the induction of low-level replicative stress.
  • This mechanism is shared with pterostilbene and hydroxyurea, highlighting a conserved cellular response.
Keywords:
CRISPR-Cas9DNA replicationSIRT1cell proliferationgenome-wide screenhuman cellshydroxyureanucleotide poolsreplicative stressresveratrol

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