Large-scale mRNA translation and the intricate effects of competition for the finite pool of ribosomes

Jain, Aditi; Margaliot, Michael; Gupta, Arvind Kumar

We present a new theoretical framework for large-scale mRNA translation using a network of models called the ribosome flow model with Langmuir kinetics (RFMLK), interconnected via a pool of free ribosomes. The input to each RFMLK depends on the pool density, and it affects the initiation rate and the internal ribosome entry rates at each site along each RFMLK. Ribosomes that detach from an RFMLK due to termination or premature drop-off are fed back into the pool. We prove that the network always converges to a steady-state, and study its sensitivity to variations in the parameters. For example, we show that if the drop-off rate at some site in some RFMLK is increased then the pool density increases and consequently the steady-state production rate in all the other RFMLKs increases. Surprisingly, we also show that modifying a parameter of a certain RFMLK can lead to arbitrary effects on the densities along the modified RFMLK, depending on the parameters in the entire network. We conclude that the competition for shared resources generates an indirect and intricate web of mutual effects between the mRNA molecules, that must be accounted for in any analysis of translation.