2'-Deoxyriboguanylurea, the primary breakdown product of 5-aza-2'-deoxyribocytidine, is a mutagen, an epimutagen, an inhibitor of DNA methyltransferases and an inducer of 5-azacytidine-type fragile sites.
2'-Deoxyriboguanylurea, the primary breakdown product of 5-aza-2'-deoxyribocytidine, is a mutagen, an epimutagen, an inhibitor of DNA methyltransferases and an inducer of 5-azacytidine-type fragile sites.
复制标题
2-Deoxyriboguanylurea 是 5-aza-2-deoxyribocytidine 的主要分解产物，是一种诱变剂、表观诱变剂、DNA 甲基转移酶抑制剂和 5-azacytidine 型脆弱位点诱导剂。
DOI：
10.1093/nar/gks706
复制
发表时间：
2012
影响因子：
14.9
通讯作者：
Smith,StevenS
中科院分区：
文献类型：
--
作者：
Lamparska,Katarzyna;Clark,Jarrod;Babilonia,Gail;Bedell,Victoria;Yip,Wesley;Smith,StevenS
5-氮杂-2 ′-脱氧胞苷（5azaC-dR）是一种DNA甲基化抑制剂、化疗药物、染色体断裂剂、诱变剂、脆性位点诱导剂和致癌剂。然而，它的作用难以量化，因为它在水溶液中迅速分解为稳定的化合物2′-脱氧核糖鸟苷脲（GuaUre-dR）。在这里，我们使用了一种亚磷酰胺，它允许在合成寡脱氧核苷酸的定义位置引入GuaUre-dR，以证明它是人DNA甲基转移酶1（hDNMT 1）和细菌DNA甲基转移酶（M.EcoRII）的有效抑制剂，并且它是一种诱变剂，可以与鸟嘌呤或胞嘧啶形成生产性碱基对。发现纯的GuaUre-dR是有效的去甲基化剂，并且能够在人细胞中诱导5azaC-dR型脆性位点FRA 1 J和FRA 9 E。此外，我们还报道了与C：G → G：C颠换和C：G → T：A转换突变相关的去甲基化作用，这些数据表明，5azaC-dR的大部分作用是通过其稳定的初级分解产物表现出来的。
5-Aza-2′-deoxycytidine (5azaC-dR) has been employed as an inhibitor of DNA methylation, a chemotherapeutic agent, a clastogen, a mutagen, an inducer of fragile sites and a carcinogen. However, its effects are difficult to quantify because it rapidly breaks down in aqueous solution to the stable compound 2′-deoxyriboguanylurea (GuaUre-dR). Here, we used a phosphoramidite that permits the introduction of GuaUre-dR at defined positions in synthetic oligodeoxynucleotides to demonstrate that it is a potent inhibitor of human DNA methyltransferase 1 (hDNMT1) and the bacterial DNA methyltransferase (M.EcoRII) and that it is a mutagen that can form productive base pairs with either Guanine or Cytosine. Pure GuaUre-dR was found to be an effective demethylating agent and was able to induce 5azaC-dR type fragile sites FRA1J and FRA9E in human cells. Moreover, we report that demethylation associated with C:G → G:C transversion and C:G → T:A transition mutations was observed in human cells exposed to pure GuaUre-dR. The data suggest that most of the effects attributed to 5azaC-dR are exhibited by its stable primary breakdown product.