ALTERED REGULATION OF MESSAGE STABILITY AND TUMOR PROMOTER-RESPONSIVECIS-TRANS INTERACTIONS OF RIBONUCLEOTIDE REDUCTASE R1 AND R2 MESSENGER-RNAS IN HYDROXYUREA-RESISTANT CELLS

Mammalian ribonucleotide reductase is a highly regulated activity esse ntial 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 thro ugh 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 h alf-lives. This was accompanied by alterations in R1 and R2 3'-untrans lated region cis-trans interactions, as judged by band shift and UV cr osslinking 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 acqu iring resistance to an antitumor agent. Furthermore, the present study strongly supports the concept that R1BP and R2BP are important genera l regulators of ribonucleotide reductase message stability and act as message destabilizing factors.