Journal
MOLECULAR CELL
Volume 79, Issue 5, Pages 846-+Publisher
CELL PRESS
DOI: 10.1016/j.molcel.2020.07.010
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Funding
- Terry Fox Foundation
- Quebec Breast Cancer Foundation
- Dr. R. John Fraser and Mrs. Clara M. Fraser Memorial Trust
- McGill University
- Canadian Institutes of Health Research (CIHR) [148936, 163051, FDN-167277]
- Genomics Technology Platform award from Genome Canada
- Genomics Technology Platform award from Genome Quebec
- Fonds de Recherche du Quebec - Nature et Technologie (FRQ-NT)
- Cole Foundation
- CIHR postdoctoral fellowship
- Junior 2 Research Scholar of Fonds de Recherche du Quebec - Sante (FRQ-S)
- FRQ-S
- Canada Research Chair in Systems and Synthetic Biology
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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 resveratrolon human cell proliferation is the induction of low-level replicative stress.
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