期刊
INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES
卷 23, 期 16, 页码 -出版社
MDPI
DOI: 10.3390/ijms23169209
关键词
G-quadruplex; G4-binding ligands; plant secondary metabolites; luciferase reporter assay; c-MYC promoter; fluorescent indicator displacement; gene expression regulation
资金
- Russian Science Foundation [21-14-00161]
Guanine-rich DNA sequences tend to adopt noncanonical G-quadruplex structures, and these sequences are over-represented in oncogene promoter regions. Plant secondary metabolites (PSMs) interact with G-quadruplexes and influence gene expression by modulating cell signaling pathways.
Guanine-rich DNA sequences tending to adopt noncanonical G-quadruplex (G4) structures are over-represented in promoter regions of oncogenes. Ligands recognizing G4 were shown to stabilize these DNA structures and drive their formation regulating expression of corresponding genes. We studied the interaction of several plant secondary metabolites (PSMs) with G4s and their effects on gene expression in a cellular context. The binding of PSMs with G4s formed by the sequences of well-studied oncogene promoters and telomeric repeats was evaluated using a fluorescent indicator displacement assay. c-MYC G4 folding topology and thermal stability, as well as the PMS influence on these parameters, were demonstrated by UV-spectroscopy and circular dichroism. The effects of promising PSMs on c-MYC expression were assessed using luciferase reporter assay and qPR-PCR in cancer and immortalized cultured cells. The ability of PMS to multi-targeting cell signaling pathways was analyzed by the pathway-focused gene expression profiling with qRT-PCR. The multi-target activity of a number of PSMs was demonstrated by their interaction with a set of G4s mimicking those formed in the human genome. We have shown a direct G4-mediated down regulation of c-MYC expression by sanguinarine, quercetin, kaempferol, and thymoquinone; these effects being modulated by PSM's indirect influence via cell signaling pathways.
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