Role of ribosomal RNA methylases in the regulation of ribosome production in mammalian cells

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Abstract
The activity of rRNA methylases was stimulated by high energy precursors of RNA (ribonucleoside triphosphates) and inhibited by degradation products of RNA (ribonucleotides and oligoribonucleotides). The response of methylases from rat Novikoff ascites hepatoma and liver to these metabolites was strikingly different. The highly active tumor enzymes responded preferentially to inhibition by catabolic metabolites, whereas the less active liver enzymes responded exclusively to stimulation by anabolic metabolites. When the activity of rRNA methylases was assayed in response to increasing concentration of S-adenoxylmethionine, the tumor enzymes responded with a hyperbolic substrate dependence curve and the liver enzymes with a sigmoidal curve. In the presence of an inhibitory dinucleotide, ApA [adenylyl adenosine], the tumor enzymes responded with a sigmoidal curve. In the presence of a stimulator, the liver enzymes responded with a hyperbolic substrate concentration curve. When normal rats were subject ot a series of treatments by thioacetamide, a hepatocarcinogen, the liver nucleolar rRNA methylases became responsive to inhibition by ApA and relatively unresponsive to stimulation by ATP. When tumor-bearing rats were treated with polyinosinate:polycytidylate, an antitumor agent, the tumor nucleolar rRNA methylases became unresponsive to inhibition by ApA and more responsive to stimulation by ATP. A correlation was noted between increased methylation efficiency in vivo and increased stability of nucleolar RNA during incubation in vitro, or vice versa. These results are interpreted to indicate that rRNA methylases are regulated by cellular metabolites during the nucleolar biosynthesis of ribosomes and that rRNA methylases ma provide a fovorable site for selective action by cancer chemotherapeutic agents.