The emergence of homeostatic mechanisms that enable maintenance of an intracellular steady state during growth was critical to the advent of cellular life. Here, we show that concentration-dependent reversible binding of short oligonucleotides, of both specific and random sequence, can modulate ribozyme activity. In both cases, catalysis is inhibited at high concentrations, and dilution activates the ribozyme via inhibitor dissociation, thus maintaining near-constant ribozyme specific activity throughout protocell growth. To mimic the result of RNA synthesis within non-growing protocells, we co-encapsulated high concentrations of ribozyme and oligonucleotides within fatty acid vesicles, and ribozyme activity was inhibited. Following vesicle growth, the resulting internal dilution produced ribozyme activation. This simple physical system enables a primitive homeostatic behaviour: the maintenance of constant ribozyme activity per unit volume during protocell volume changes. We suggest that such systems, wherein short oligonucleotides reversibly inhibit functional RNAs, could have preceded sophisticated modern RNA regulatory mechanisms, such as those involving miRNAs.
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The authors thank K.A. Bj?rkbom, T. Walton, N. Kamat, C. Hentrich, L. Jin and other Szostak laboratory members for discussions. This work was supported in part by NASA Exobiology grant NNX11AD56G to J.W.S. and a grant (290363) from the Simons Foundation to J.W.S. A.E.E. was supported by an appointment to the NASA Postdoctoral Program, administered by Oak Ridge Associated Universities through a contract with NASA, and by a Tosteson Fellowship from the Massachusetts General Hospital Executive Committee on Research. J.W.S. is an Investigator of the Howard Hughes Medical Institute.