Depletion of Cellular Iron by Curcumin Leads to Alteration in Histone Acetylation and Degradation of Sml1p in Saccharomyces cerevisiae

Abstract

Curcumin, a naturally occurring polyphenolic compound, is known to possess diverse pharmacological properties. There is a scarcity of literature documenting the exact mechanism by which curcumin modulates its biological effects. In the present study, we have used yeast as a model organism to dissect the mechanism underlying the action of curcumin. We found that the yeast mutants of histone proteins and chromatin modifying enzymes were sensitive to curcumin and further supplementation of iron resulted in reversal of the changes induced by curcumin. Additionally, treatment of curcumin caused the iron starvation induced expression of FET3, FRE1 genes. We also demonstrated that curcumin induces degradation of Sml1p, a ribonucleotide reductase inhibitor involved in regulating dNTPs production. The degradation of Sml1p was mediated through proteasome and vacuole dependent protein degradation pathways. Furthermore, curcumin exerts biological effect by altering global proteome profile without affecting chromatin architecture. These findings suggest that the medicinal properties of curcumin are largely contributed by its cumulative effect of iron starvation and epigenetic modifications.

Yeast Dun1 Kinase Regulates Ribonucleotide Reductase Inhibitor Sml1 in Response to Iron Deficiency

“…4A, the drop in Sml1 protein caused by low Fe is impaired in the pre1-1 strain compared to the wild-type strain, suggesting that the Sml1 protein is degraded by the 26S proteasome in response to Fe deficiency. This result is consistent with the inhibition of Sml1 protein degradation observed when the proteasome inhibitor MG132 is added to curcumin-treated yeast cells (62).…”

“…4). These results are consistent with recent observations by other groups showing that Sml1 degradation induced by HU occurs in a Pep4-independent manner (68), whereas Sml1 diminution induced by curcumin is defective in the presence of MG132 or PMSF, inhibitors of the proteasomal and vacuolar proteolytic pathways, respectively (62). All these results indicate that both the 26S proteasome and the vacuolar proteolytic pathway contribute to the degradation of the Sml1 protein in response to Fe starvation, whereas the proteasome-dependent pathway is the major mechanism of Sml1 degradation in the DNA damage response.…”

“…In response to genotoxic stress, Dun1 kinase promotes RNR function through multiple mechanisms, including transcriptional RNR2, RNR3, and RNR4 derepression, redistribution of the small R2 subunit from the nucleus to the cytoplasm, and degradation of the R1 inhibitor Sml1 (4). A recent study has shown that curcumin, a polyphenolic compound, extracted from the Indian spice turmeric, with diverse biological effects, including Fe chelation, promotes the degradation of the large R1 subunit inhibitor Sml1 in budding yeast (62). Therefore, we decided to ascertain whether Sml1 protein abundance is in- (22,23).…”

“…The degradation of the Sml1 protein by curcumin treatment is inhibited by the addition of the vacuolar proteolysis inhibitor phenylmethylsulfonyl fluoride (PMSF) (62). To further investigate whether the vacuolar proteolytic pathway is involved in the degradation of Sml1 by Fe deficiency, we determined Sml1 protein levels in cells lacking Pep4 vacuolar proteinase A, which is required for the posttranslational maturation of other vacuolar proteases (reviewed in reference 67).…”

Impaired mitochondrial Fe-S cluster biogenesis activates the DNA damage response through different signaling mediators

“…By contrast, WTM1 mRNA levels are destabilized in response to iron scarcity by the mRNA-binding protein Cth2 (Sanvisens et al, 2011). In addition, RNR is activated in iron-limited conditions (Azad et al, 2013;Sanvisens et al, 2014) in a Dun1-dependent but Mec1-and Rad53-independent manner (Sanvisens et al, 2014).…”