Sergeev, A.V.; Loiko, A.G.; Genatullina, A.I.; Petrov, A.S.; Kubareva, E.A.; Dolinnaya, N.G.; Gromova, E.S. Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter. Int. J. Mol. Sci.2024, 25, 45.
Sergeev, A.V.; Loiko, A.G.; Genatullina, A.I.; Petrov, A.S.; Kubareva, E.A.; Dolinnaya, N.G.; Gromova, E.S. Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter. Int. J. Mol. Sci. 2024, 25, 45.
Sergeev, A.V.; Loiko, A.G.; Genatullina, A.I.; Petrov, A.S.; Kubareva, E.A.; Dolinnaya, N.G.; Gromova, E.S. Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter. Int. J. Mol. Sci.2024, 25, 45.
Sergeev, A.V.; Loiko, A.G.; Genatullina, A.I.; Petrov, A.S.; Kubareva, E.A.; Dolinnaya, N.G.; Gromova, E.S. Crosstalk between G-Quadruplexes and Dnmt3a-Mediated Methylation of the c-MYC Oncogene Promoter. Int. J. Mol. Sci. 2024, 25, 45.
Abstract
Methylation of cytosines at CpG sites in DNA, carried out by de novo by DNA methyltransferase Dnmt3a, is a basic epigenetic modification involved in gene regulation and genome stability. Aberrant CpG methylation in gene promoters leads to oncogenesis. In oncogene promoters, CpG sites often colocalize with guanine-rich sequences capable of folding into G-quadruplexes (G4s). Our in vitro study aimed to investigate how parallel G4s formed by a sequence derived from the c-MYC oncogene promoter region affect the activity of the Dnmt3a catalytic domain (Dnmt3a-CD). For this purpose, we designed synthetic oligonucleotide constructs: c-MYC G4-forming oligonucleotide and linear double-stranded DNA containing an embedded stable extrahelical c-MYC G4. The topology and thermal stability of G4 structures in these DNA models were analyzed by physicochemical techniques. We showed that Dnmt3a-CD specifically binds to an oligonucleotide containing c-MYC G4, resulting in inhibition of its methylation activity. c-MYC G4 formation in a double-stranded context significantly reduce Dnmt3a-CD-induced methylation of a CpG site located in close proximity to the quadruplex structure; this effect depends on the distance between the non-canonical structure and the specific CpG site. One would expect DNA hypomethylation near the G4 structure, while regions distant from this non-canonical form would maintain a regular pattern of high methylation levels. We hypothesize that the G4 structure sequesters the Dnmt3a-CD and impedes its proper binding to B-DNA, resulting in hypomethylation and activation of c-MYC transcription.
Keywords
G-quadruplexes; c-MYC promoter, DNA methylation; Dnmt3a; DNA-protein interaction
Subject
Biology and Life Sciences, Life Sciences
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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