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Altered Regulation of Message Stability and Tumor Promoter-responsive cis-trans Interactions of Ribonucleotide Reductase R1 and R2 Messenger RNAs in Hydroxyurea-resistant Cells¹

Manitoba Institute of Cell Biology and Department of Biochemistry and Molecular Biology, University of Manitoba, Winnipeg, Manitoba, R3E 0V9 Canada

Mammalian ribonucleotide reductase is a highly regulated activity essential for DNA synthesis and repair. The activity and message levels of the enzyme are elevated in cells treated with the tumor promoter 12-O-tetradecanoylphorbol-13-acetate, and this appears to be mediated through specific cis elements in the 3'-untranslated region of the R1 and R2 mRNAs that interact with R1 and R2 binding proteins called R1BP and R2BP, respectively. Hydroxyurea-resistant cells with increased R1 and R2 message levels were observed to have increased R1 and R2 message half-lives. This was accompanied by alterations in R1 and R2 3'-untranslated region cis-trans interactions, as judged by band shift and UV cross-linking assays, in which R1BP and R2BP binding was markedly reduced. This first description of mutant mammalian cells altered in message stability regulatory determinants indicates another mechanism for acquiring resistance to an antitumor agent. Furthermore, the present study strongly supports the concept that R1BP and R2BP are important general regulators of ribonucleotide reductase message stability and act as message destabilizing factors.

¹ This investigation was supported by operating grants from the National Cancer Institute of Canada and the Natural Sciences and Engineering Research Council of Canada (to J. A. W.). F. M. A. and A. H. thank the Manitoba Cancer Treatment and Research Foundation and the H. E. Sellers Foundation for postdoctoral fellowship support. J. A. W. is a Terry Fox Senior Scientist of the National Cancer Institute of Canada.

² To whom requests for reprints should be addressed, at Manitoba Institute of Cell Biology, 100 Olivia Street, Winnipeg, Manitoba, R3E 0V9 Canada. Phone: (204) 787-4128; Fax: (204) 787-2190.

Received 7/25/95. Accepted 8/28/95.

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