Wright Elisé P, Lamparska Katarzyna, Smith Steven S, Waller Zoë A E
School of Pharmacy, University of East Anglia , Norwich Research Park, Norwich NR4 7TJ, U.K.
Beckman Research Institute and Division of Urology, City of Hope , 1500 East Duarte Road, Duarte, California 91010-3000, United States.
Biochemistry. 2017 Sep 12;56(36):4879-4883. doi: 10.1021/acs.biochem.7b00628. Epub 2017 Aug 30.
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.
5-氮杂-2'-脱氧胞苷（地西他滨）及其主要分解产物2'-脱氧核糖鸟嘌呤脲（GuaUre-dR）均已被证明可作为诱变剂和表位诱变剂，引起复制应激并改变DNA甲基化和基因表达模式。作为胞嘧啶类似物，预计两者都会优先掺入GC偏斜区域，其中胞嘧啶残基的序列在一条链上被隔离，而鸟嘌呤残基在另一条链上。鉴于此类区域已被确定为可能影响基因表达和与形成替代DNA二级结构相关的复制应激的位点，确定这些碱基类似物可能对这类结构的稳定性产生的影响是很有意义的。在此我们报告，尽管GuaUre-dR明显具有与胞嘧啶碱基配对的能力，但将其掺入形成i-基序的序列中会降低i-基序的热稳定性和pH稳定性。
