N<SUP>4</SUP>-アミノシチジンによる突然変異の機構

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タイトル別名
  • Molecular Mechanism of N<SUP>4</SUP>-Aminocytidine Mutagenesis
  • N4-アミノシチジンによる突然変異の機構
  • N4 アミノシチジン ニ ヨル トツゼン ヘンイ ノ キコウ

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説明

N4-Aminocytidine is strongly mutagenic towards E. coli, S. typhimurium, B. subtilis and coliphages φX174 and M13mp2. It also causes mutations in mammalian cell lines and somatic cell mutations in D. melanogaster. The sequence analysis of deoxyribonucleic acid (DNA) from mutated phages revealed that N4-aminocytidine induces both adeninethymine (AT) to guanine-cytosine (GC) and GC to AT transitions. No transversions are detectable. When E. coli and the mammalian cells were cultured in the presence of [3H]-N4-aminocytidine, [3H]-N4-aminodeoxycytidine was found in their DNA. It is likely that N4-aminocytidine is metabolized within the cells into N4-aminodeoxycytidine 5'-triphosphate (dCamTP), which is then incorporated into DNA, thereby causing base-pair transitions. To prove this hypothesis, we studied the incorporation of dCamTP into polynucleotides in the in vitro DNA synthesis catalyzed by E. coli DNA polymerase I large fragment (Klenow enzyme) and DNA polymerase α from a mouse cell line. Both polymerases catalyze incorporation of dCamTP into DNA efficiently in place of dCTP opposite guanine, and less efficiently, but to a significant extent, in place of dTTP opposite adenine. These observations prove the erroneous nature of dCamTP as a substrate for DNA synthesis. DNA containing N4-aminocytosine was prepared by the incorporation of dCamTP into single-stranded phage DNA annealed to complementary oligonucleotides. The DNA was transfected to E. coli cells. The analysis of progeny phages indicates that N4-aminocytosine residue in DNA causes A to G or G to A mutation in the position opposite to the site where N4-aminocytosine should be incorporated.

収録刊行物

  • 薬学雑誌

    薬学雑誌 110 (5), 293-303, 1990

    公益社団法人 日本薬学会

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