Abstract
N6-methyladenine modification (m6dA) has recently been identified in eukaryote genomic DNA. The methylation destabilizes the duplex structure when the adenine forms a Watson–Crick base pair, whereas the methylation on a terminal unpaired adenine stabilizes the duplex structure by increasing the stacking interaction. In this study, the effects of m6dA modification on the thermal stability of four distinct telomeric G-quadruplex (G4) structures were investigated. The m6dA-modified telomeric oligonucleotide d[AGGG(TTAGGG)3] that forms a basket-type G4 in Na+, d[(TTAGGG)4TT] that forms a hybrid-type G4 in K+ (Form-2), d[AAAGGG(TTAGGG)3AA] that forms a hybrid-type G4 in K+ (Form-1), and d[GGG(TTAGGG)3T] that forms a basket-type G4 with two G-tetrads in K+ (Form-3) were analyzed. Circular dichroism melting analysis demonstrated that (1) A7- and A19-methylation destabilized the basket-type G4 structure that formed in Na+, whereas A13-methylation stabilized the structure; (2) A15-methylation stabilized the Form-2 G4 structure; (3) A15- and A21-methylations stabilized the Form-1 G4 structure; and (4) A12-methylation stabilized the Form-3 G4 structure. These results suggest that m6dA modifications may affect the thermal stability of human telomeric G4 structures in regulating the biological functions.
Highlights
A human telomere consists of a tract of tandemly repeated short DNA sequences d(TTAGGG) with a single-stranded overhang at the extreme 30 end and protective proteins [1]
G4 ligands stabilize the telomeric G4 structure and inhibit the telomerase activity in cancer cells [5]; identification of factors that affect the stability of the telomeric G4 structure is important for understanding telomere biology, which can lead to applications in anti-cancer drug development
Thermal stabilities were analyzed with circular dichroism (CD) spectra measurements
Summary
A human telomere consists of a tract of tandemly repeated short DNA sequences d(TTAGGG) with a single-stranded overhang at the extreme 30 end and protective proteins [1]. The single-stranded overhang can form G-quadruplex (G4) structures, which are non-canonical nucleic acid structure formed due to the stacking of G-tetrads [3]. The long telomeric oligonucleotide repeat-forms a bead-on-a-string structure in which the G4 units are connected by one TTA [4]. G4 ligands stabilize the telomeric G4 structure and inhibit the telomerase activity in cancer cells [5]; identification of factors that affect the stability of the telomeric G4 structure is important for understanding telomere biology, which can lead to applications in anti-cancer drug development.
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