Genome-wide screens reveal that resveratrol induces replicative stress in human cells
Published on August 6, 2020
Pinpointing the effects of resveratrol on human cells
Resveratrol (RSV) is a natural compound found in many plants, including the skin of grapes (and in wine), blueberries, raspberries, mulberries and peanuts. It has attracted considerable research attention due to its reported beneficial properties in experimental models such as yeasts, nematode worms, fruit flies and mice, including lifespan extension under certain conditions. A causal role of RSV in human health has not yet been established.
These and other previous studies of RSV, and its chemical analogues such as pterostilbene (PTS), illustrated an ability of these compounds to activate or inhibit numerous cellular processes, including those mediated by the histone deacetylase sirtuin 1 (SIRT1). The diversity of these effects suggests that the targets of RSV in humans may not yet be fully defined.
Interrogating the human genome to identify the mechanisms of action of RSV
Yahya Benslimane, a PhD student in Lea Harrington’s group at IRIC, in collaboration with Mike Tyers’ group at IRIC and colleagues at the Research Center of Maisonneuve Rosemont Hospital, the Lady Davis Research Institute and the Goodman Cancer Center at McGill University, recently undertook an unbiased and systematic examination of the genetic targets of RSV and PTS in human cells. Their results uncovered that RSV inhibits cell proliferation by targeting DNA replication. Their findings were just published in the journal Molecular Cell.
RSV induces replicative stress in human cells
The group used CRISPR-Cas9 gene editing technology to identify genes, across the entire human genome, that enhance or inhibit the effects of RSV and PTS on the proliferation of two human cell lines in culture. They found that cells treated with RSV and PTS shared a profile of genes that were largely involved in DNA replication and the maintenance of genome integrity. Furthermore, the genetic profiles of RSV and PTS overlapped with that of hydroxyurea (HU) a well-characterized inducer of replicative stress due to its depletion of dNTPs, the building blocks of DNA. The researchers then confirmed that upon RSV or PTS treatment, the pool of intracellular dNTPs was sufficiently depleted to impede DNA synthesis and delay cell cycle progression. They also showed that the growth inhibition induced by RSV or PTS was exacerbated by other replicative-stress inducing treatments, but was unaffected by the absence of the histone deacetylase SIRT1.
This study is the first instance in which the cellular effects of RSV and PTS on DNA replication were identified in an unbiased manner using genome-wide screens. It demonstrates that a major impact of RSV on human cells is the induction of replicative stress, and points to the need to further examine the potential role(s) of these plant compounds on human cells and tissues.
Benslimane Y, Bertomeu T, Coulombe-Huntington J, McQuaid M, Sánchez-Osuna M, Papadopoli D, Avizonis D, De Sa Tavares Russo M, Huard C, Topisirovic I, Wurtele H, Tyers M, Harrington L
Molecular Cell. 2020 August