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Vol. 56, Issue 4, 841-848, October 1999

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

St. Jude Children's Research Hospital, and Colleges of Pharmacy and Medicine, University of Tennessee, Memphis, Tennessee (N.F.K., E.Y.K., W.E.E.); and Chemistry Department, Moscow State University, Moscow, Russia (N.F.K.)

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 dGs incorporation 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.

Copyright © 1999 by The American Society for Pharmacology and Experimental Therapeutics


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