Resveratrol and its Related Polyphenols Contribute to the Maintenance of Genome Stability

Abstract

Genomic destabilisation is associated with the induction of mutations, including those in cancer-driver genes, and subsequent clonal evolution of cells with abrogated defence systems. Such mutations are not induced when genome stability is maintained; however, the mechanisms involved in genome stability maintenance remain elusive. Here, resveratrol (and related polyphenols) is shown to enhance genome stability in mouse embryonic fibroblasts, ultimately protecting the cells against the induction of mutations in the ARF/p53 pathway. Replication stress-associated DNA double-strand breaks (DSBs) that accumulated with genomic destabilisation were effectively reduced by resveratrol treatment. In addition, resveratrol transiently stabilised the expression of histone H2AX, which is involved in DSB repair. Similar effects on the maintenance of genome stability were observed for related polyphenols. Accordingly, we propose that polyphenol consumption can contribute to the suppression of cancers that develop with genomic instability, as well as lifespan extension. Most cancers are associated with genomic instability, which can be categorised as chromosomal instability or microsatellite instability (MSI) 1. Genomic destabilisation is a major cause of mutations, including those in cancer-driver genes, and can lead to clonal evolution of cells with abrogated defence systems, such as those containing mutations in the ARF/p53 pathway 2. Genome stability maintenance would likely prevent the formation of mutations and suppress cancer development; however, it is still unclear if genome stability can be maintained in vivo and whether this process can indeed suppress the occurrence of cancer. Genomic instability is caused by the erroneous repair of DNA double-strand breaks (DSBs); paradoxically, the DNA repair systems of most cancers that develop with genomic instability are genetically normal 3. The mechanisms by which normal cells accumulate DSBs remain unclear, but DSBs widely accumulate in pre-cancerous cells and are accompanied by genomic instability 2,4-6. In vitro, replication stress-associated DSBs and the associated genomic instability are observed in cells subjected to aberrant growth stimulation 2 or overexpression of oncogenes such as c-Myc and E2F1 6-8. Possibly reflecting the correlation between cancer development and age, DSBs accumulate with age in vivo and with cultivating passages in vitro 9 , suggesting that ageing cells are defective in DSB repair. DSB repair deficiency is probably related at least in part to a reduction in the level of H2AX. This histone mediates DSB repair and is required for genome stability maintenance, and H2AX expression levels are attenuated when the growth rate of normal cells slows down 10,11. In fact, such cells are defective in repairing replication stress-associated DSBs 10 ,

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

“…Overexpression of the yeast sirtuin ortholog Sir2 or the DNA replication/recombination RAP1-interacting factor Rif1 extends replicative lifespan (Hoopes et al, 2002;Kaeberlein et al, 1999Kaeberlein et al, , 2004Kwan et al, 2013;Salvi et al, 2013) and also regulate DNA replication origins at the rDNA locus and elsewhere (Cornacchia et al, 2012;Hafner et al, 2018;Hiraga et al, 2018;Mukherjee et al, 2019;Salvi et al, 2013;Shyian et al, 2016;Yamazaki et al, 2012). Recently, low doses of RSV (2.5 mM) were found to protect genome stability via a reduction in replication stress-associated DSBs in murine 3T3 cells (Matsuno et al, 2020). It is possible that RSV might elicit a type of hormesis (Agathokleous and Calabrese, 2019;Stebbing, 1982), whereby low-level replicative stress may be beneficial in some contexts but deleterious in others.…”

Natural Compounds That Target DNA Repair Pathways and Their Therapeutic Potential to Counteract Cancer Cells

“…As an anticancer compound, low-dose resveratrol accelerates non-mutagenic repair of DNA damage in mouse embryonic stem cells exposed to ionizing radiation (14). Similarly, resveratrol in mouse embryonic fibroblasts was shown to help maintain genomic stability after chemical and ionizing radiation damage by allowing greater repair efficiency of double-strand breaks and less replicative stress (15). Furthermore, resveratrol was shown to significantly reduce DNA damage from arsenic compounds in non-cancerous mammalian cells by enhancing repair activities, especially if used prior to exposure (16).…”

Resveratrol: Friend or Foe?

“…Understanding the mechanisms driving the replication stress response in cells treated with RSV and PTS will be critical, especially in the context of these compounds being used as nutritional supplements for the purpose of increasing lifespan. In this context, a recent report has suggested a genome protective benefit with low doses (2.5 mM) of RSV (Matsuno et al, 2020). In light of the discoveries presented here by Benslimane et al (2020), it will be important to consider potential safety concerns of increased doses of these compounds in people with increased susceptibility to genomic instability.…”