Selective inhibition of the 3′ to 5′ exonuclease activity associated with DNA polymerases: A mechanism of mutagenesis

John Byrnes, Kathleen M. Downey, Benito G. Que, Marietta Y W Lee, Vicky L. Black, Antero G. So

Research output: Contribution to journalArticle

68 Citations (Scopus)

Abstract

The 3′ to 5′ exonuclease activity associated with both mammalian and bacterial DNA polymerases can be selectively inhibited by nucleoside 5′-monophosphates including 6-mercaptopurine ribonucleoside 5′-monophosphate, whereas the polymerase activity is not affected. Nucleosides, 3′ nucleotides, and cyclic nucleotides have no effect on exonuclease activity. With poly(dA-dT) as a template/primer both Escherichia coli DNA polymerase I and mammalian DNA polymerase δ catalyze the template-dependent conversion of deoxyribonucleoside triphosphate to monophosphate with the noncomplementary nucleotides dGTP and dCTP. This represents the incorporation of the noncomplementary nucleotide at the primer terminus by the polymerase activity and its subsequent hydrolysis by the proofreading exonuclease activity. Selective inhibition of the exonuclease activity results in a decrease in the amount of free dGMP or dCMP generated and an increase in the amount of dGMP or dCMP incorporated into poly(dA-dT), and, thus, to a higher error frequency. 6-Mercaptopurine is a known mutagen in E. coli and its derivative, Azathioprine, is a mutagen in Salmonella typhimurium and a carcinogen in man. Azathioprine is readily converted to 6-mercaptopurine in vivo. It is proposed that the mutagenicity of 6-mercaptopurine and Azathioprine in microorganisms and their carcinogenicity in man are due to the selective inhibition of the proofreading exonuclease associated with DNA polymerases by 6-mercaptopurine ribonucleoside 5′-monophosphate, the active metabolite of 6-mercaptopurine. This would result in a higher frequency of mispaired bases in DNA and consequent mutation.

Original languageEnglish
Pages (from-to)3740-3746
Number of pages7
JournalBiochemistry
Volume16
Issue number17
StatePublished - Dec 1 1977

Fingerprint

Phosphodiesterase I
6-Mercaptopurine
Exonucleases
Mutagenesis
Azathioprine
DNA-Directed DNA Polymerase
Poly dA-dT
Mutagens
Nucleosides
Nucleotides
Escherichia coli
Deoxyribonucleosides
Bacterial DNA
DNA Polymerase I
Salmonella
Cyclic Nucleotides
Metabolites
Microorganisms
Carcinogens
Hydrolysis

ASJC Scopus subject areas

  • Biochemistry

Cite this

Byrnes, J., Downey, K. M., Que, B. G., Lee, M. Y. W., Black, V. L., & So, A. G. (1977). Selective inhibition of the 3′ to 5′ exonuclease activity associated with DNA polymerases: A mechanism of mutagenesis. Biochemistry, 16(17), 3740-3746.

Selective inhibition of the 3′ to 5′ exonuclease activity associated with DNA polymerases : A mechanism of mutagenesis. / Byrnes, John; Downey, Kathleen M.; Que, Benito G.; Lee, Marietta Y W; Black, Vicky L.; So, Antero G.

In: Biochemistry, Vol. 16, No. 17, 01.12.1977, p. 3740-3746.

Research output: Contribution to journalArticle

Byrnes, J, Downey, KM, Que, BG, Lee, MYW, Black, VL & So, AG 1977, 'Selective inhibition of the 3′ to 5′ exonuclease activity associated with DNA polymerases: A mechanism of mutagenesis', Biochemistry, vol. 16, no. 17, pp. 3740-3746.
Byrnes, John ; Downey, Kathleen M. ; Que, Benito G. ; Lee, Marietta Y W ; Black, Vicky L. ; So, Antero G. / Selective inhibition of the 3′ to 5′ exonuclease activity associated with DNA polymerases : A mechanism of mutagenesis. In: Biochemistry. 1977 ; Vol. 16, No. 17. pp. 3740-3746.
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