Abstract
Both 5-aza-2'-deoxycytidine (decitabine) and its primary breakdown product, 2'-deoxyriboguanylurea (GuaUre-dR), have been shown to act as mutagens and epimutagens that cause replication stress and alter both DNA methylation and gene expression patterns. As cytosine analogues, both are expected to be preferentially incorporated into regions of GC skew where runs of cytosine residues are sequestered on one strand and guanine residues on the other. Given that such regions have been identified as sites with the potential for effects on gene expression and replication stress linked to formation of alternative DNA secondary structures, it is of interest to determine the influence that these base analogues might have on the stability of structures of this kind. Here we report that incorporation of GuaUre-dR into an i-motif-forming sequence decreases both the thermal and pH stability of an i-motif despite the apparent ability of GuaUre-dR to base pair with cytosine.
Highlights
The nucleoside drug decitabine, 5-aza-2′-deoxycytidine, has been identified as an epimutagen and a chemotherapeutic.[1,2] It has been found to induce fragile sites in DNA, inhibit
While the formation of a covalent bond between DNMT1 and 5azaC-dR-treated DNA could be ruled out as a cause of proteolysis, the mechanism by which DNMT1 is targeted for degradation is not yet well understood.[6]
It is known that noncanonical DNA structures rich in cytosine are targeted by DNMT1.7 This interaction results in methylated CG dinucleotides at sites of abnormal base pairing that bind to and trap the DNMT1 enzyme in tight DNA complexes.[8−11] An interaction with a noncanonical DNA structure, such as a hairpin or an i-motif (C-quadruplex), could trap the enzyme and provide an additional trigger for the proteolysis of DNMT1
Summary
The nucleoside drug decitabine, 5-aza-2′-deoxycytidine, has been identified as an epimutagen and a chemotherapeutic.[1,2] It has been found to induce fragile sites in DNA, inhibit. UV spectroscopy experiments were performed as described previously.[21] Briefly, a Cary 60 UV−visible spectrometer (Agilent Technologies) equipped with a TC1 Temperature Controller (Quantum Northwest) was used to measure the absorbance of a 2.5 μM ODN sample at a specific pH in a small-volume masked quartz cuvette (1 cm path length). The pH and thermal stability of two ODN sequences based on the human telomeric i-motif were examined to determine the effect of GuaUre-dR modification on i-motif formation.
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