title: 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.
abstract: 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.
authors: Beckman Research Institute and Division of Urology and Urologic Oncology, City of Hope, 1500 E. Duarte Rd., Duarte, CA 91010-3000, USA.
authors: Katarzyna
authors: K
authors: Lamparska
authors: Jarrod
authors: J
authors: Clark
authors: Gail
authors: G
authors: Babilonia
authors: Victoria
authors: V
authors: Bedell
authors: Wesley
authors: W
authors: Yip
authors: Steven S
authors: SS
authors: Smith
mesh_terms: D001374:Azacitidine / Q000031:analogs & derivatives / Q000633:toxicity; D001483:Base Sequence; D045744:Cell Line, Tumor; D043283:Chromosome Fragile Sites; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000037:antagonists & inhibitors; D015254:DNA Modification Methylases / Q000037:antagonists & inhibitors*; D015257:DNA-Cytosine Methylases / Q000037:antagonists & inhibitors; D000077209:Decitabine; D003855:Deoxyribose / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D006146:Guanidines / Q000737:chemistry / Q000494:pharmacology / Q000633:toxicity*; D006801:Humans; D008969:Molecular Sequence Data; D016296:Mutagenesis; D009153:Mutagens / Q000737:chemistry / Q000633:toxicity*; D009838:Oligodeoxyribonucleotides / Q000737:chemistry
chemical_list: C577315:2'-deoxyriboguanylurea; D004791:Enzyme Inhibitors; D006146:Guanidines; D009153:Mutagens; D009838:Oligodeoxyribonucleotides; D003855:Deoxyribose; D000077209:Decitabine; D015254:DNA Modification Methylases; C029528:DNA modification methylase EcoRII; D015257:DNA-Cytosine Methylases; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; D001374:Azacitidine