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Molecular Pharmacology

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Research ArticleArticle

Human RNase H-Mediated RNA Cleavage from DNA-RNA Duplexes Is Inhibited by 6-Deoxythioguanosine Incorporation into DNA

Natalia F. Krynetskaia, Eugene Y. Krynetski and William E. Evans
Molecular Pharmacology October 1999, 56 (4) 841-848;
Natalia F. Krynetskaia
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Eugene Y. Krynetski
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William E. Evans
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Abstract

Mercaptopurine and thioguanine are anticancer and immunosuppressive agents that exert their primary cytotoxic effects via incorporation of deoxythioguanosine (dGs) into DNA, but the precise mechanism(s) by which this causes cytotoxicity remains unknown. We initially determined that the level of dGs incorporation into DNA of human T- and B-lineage leukemia cell lines did not correlate significantly with the extent of cytotoxicity (IC50), except that there was no cytotoxicity in the absence of dGs incorporation. To elucidate biological processes perturbed by dGs incorporation into DNA, we chemically synthesized oligodeoxyribonucleotides containing a single dGs (11 mer and 19 mer), which decreased the melting temperature (Tm) of DNA-DNA duplexes without major structural changes, as evidenced by circular dichroism spectra. Using nuclear extracts from human lymphoblastic leukemia cells (CCRF-CEM, NALM6, and Molt4), we documented that dGsincorporation into the DNA strand of DNA-RNA heteroduplexes significantly inhibited human RNase H-catalyzed RNA cleavage (80–90% inhibition) and that a similar inhibition was evident with bacterial RNase H. These data provide the first evidence that thiopurines inhibit the function of RNase H, indicating that their mechanism of cytotoxicity may involve interference with this component of the replication machinery.

Footnotes

  • Send reprint requests to: Dr. William E. Evans, St. Jude Children’s Research Hospital, 332 N. Lauderdale St., Memphis, TN 38105. E-mail: william.evans{at}stjude.org

  • Abbreviations:
    MP
    6-mercaptopurine
    TG
    6-thioguanine
    dGS
    6-deoxythioguanosine
    RNase H
    ribonuclease H
    HPRT
    hypoxanthine-guanine phosphoribosyl transferase
    TPMT
    thiopurine methyltransferase
    DTT
    dithiothreitol (treo-1,4-dimercapto-2,3-butanediol)
    PAAG
    polyacrylamide gel
    AMCA
    N-[6-(7-amino-4-methylcoumarin-3-acetamido)hexyl]-3′-(2′-pyridyldithio)-propionamide
    • Received April 5, 1999.
    • Accepted July 14, 1999.
  • The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 56 (4)
Molecular Pharmacology
Vol. 56, Issue 4
1 Oct 1999
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Research ArticleArticle

Human RNase H-Mediated RNA Cleavage from DNA-RNA Duplexes Is Inhibited by 6-Deoxythioguanosine Incorporation into DNA

Natalia F. Krynetskaia, Eugene Y. Krynetski and William E. Evans
Molecular Pharmacology October 1, 1999, 56 (4) 841-848;

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Research ArticleArticle

Human RNase H-Mediated RNA Cleavage from DNA-RNA Duplexes Is Inhibited by 6-Deoxythioguanosine Incorporation into DNA

Natalia F. Krynetskaia, Eugene Y. Krynetski and William E. Evans
Molecular Pharmacology October 1, 1999, 56 (4) 841-848;
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