Regulation of Hemoglobin Synthesis: PREFERENTIAL INHIBITION OF α AND β GLOBIN SYNTHESIS

Abstract

Abstract A large number of synthetic polynucleotides and polydeoxyribonucleotides inhibit globin synthesis in cell-free extracts of rabbit reticulocytes; these include poly(rU), poly(rI), poly(rA), poly(dT), poly(dC), poly(dI) and poly(rU, rI). We show that all inhibit by blocking initiation of new chains, and have no effect on the rate of completion of nascent chains. Without exception all polymers inhibit preferentially initiation of α chain synthesis. One interesting possibility is that ribosomes normally are heterogenous in their ability to translate α and β globin mRNA, and that polynucleotides preferentially inhibit α-specific ribosomes. Alternatively, polynucleotides might interact with ribosomes so as to alter their ability to recognize the initiation sequences on the two mRNAs. When the concentration of magnesium ion used in reticulocyte cell-free synthesis is 5 mm rather than the optimal 1.5 mm, there is preferential inhibition of production of β globin chains; the ratio of α to β chains produced is 2:1. Raising the concentration of magnesium resembles in its effects addition of antibiotics which preferentially inhibit elongation of polypeptide chains and also preferentially inhibit β chain synthesis. Both result in more ribosomes than normal on each mRNA. Under such conditions initiation of protein synthesis is no longer a rate-limiting step and the relative production of proteins is proportional only to the relative amounts of messenger RNA. We also discuss some long range therapeutic implications of this work in treatment of thalassemia.