Abstract
Evidences from more than three decades of work support the function of non-duplex DNA structures called G-quadruplex (G4) in important processes like transcription and replication. In addition, G4 structures have been studied in connection with DNA base modifications and chromatin/nucleosome arrangements. Recent work, interestingly, shows promise of G4 structures, through interaction with G4 structure-interacting proteins, in epigenetics—in both DNA and histone modification. Epigenetic changes are found to be intricately associated with initiation as well as progression of cancer. Multiple oncogenes have been reported to harbor the G4 structure at regulatory regions. In this context, G4 structure-binding ligands attain significance as molecules with potential to modify the epigenetic state of chromatin. Here, using examples from recent studies we discuss the emerging role of G4 structures in epigenetic modifications and, therefore, the promise of G4 structure-binding ligands in epigenetic therapy.
Highlights
DNA-protein interactions package genomic DNA into globular chromatin
Epigenetic drugs include compounds that bind to proteins that affect chromatin organization, such as histone methylation/demethylation inhibitors, bromo-domain inhibitors, HAT inhibitors, HDAC inhibitors, and DNA methyltransferase inhibitors: many of which are at different stages of clinical trials as anti-cancer molecules [75,76,77]
We focus on G4 structure-binding ligands that could be relevant in epigenetics
Summary
DNA-protein interactions package genomic DNA into globular chromatin. This along with modifications of nucleic acids—for example, methylation of cytosine residues—that otherwise do not affect the sequence of chromosomal DNA constitute the epigenetic state of the genome [1] Modifications of the epigenetic status are closely associated with several diseases including cancer, neurodegenerative and metabolic disorders and autoimmune diseases [2,3,4,5,6]. BCL-2 [30], RET [31,32], PARP-1 [33,34] These epigenetic modifications were shown to be regulated by epigenetic modifiers such as DNA methyltransferases (DNMTs) and polycomb group (PcG) proteins, like EZH2, which has been reported to bind to G4 structures in vitro and in vivo respectively [35,36,37] (vide infra). This indicates the possibility that G4 structures could potentially recruit epigenetic modifiers. We focus reviewing literature on how G4 structure-binding molecules and proteins might be important for development of epigenetic therapeutic interventions in future, in cancer
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