TY - JOUR
T1 - Large-scale mRNA translation and the intricate effects of competition for the finite pool of ribosomes
AU - Jain, Aditi
AU - Margaliot, Michael
AU - Gupta, Arvind Kumar
N1 - Publisher Copyright:
© 2022 The Authors. Published by the Royal Society under the terms of the Creative Commons Attribution License.
PY - 2022
Y1 - 2022
N2 - 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 potentially also the internal ribosome entry rates along each RFMLK. Ribosomes that detach from an RFMLK owing 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.
AB - 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 potentially also the internal ribosome entry rates along each RFMLK. Ribosomes that detach from an RFMLK owing 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.
KW - context dependence in mRNA translation
KW - cooperative dynamical systems
KW - entrainment
KW - internal ribosome entry sites
KW - mathematical modelling of competition for shared resources
KW - ribosome drop-off
UR - http://www.scopus.com/inward/record.url?scp=85126079057&partnerID=8YFLogxK
U2 - 10.1098/rsif.2022.0033
DO - 10.1098/rsif.2022.0033
M3 - מאמר
C2 - 35259953
AN - SCOPUS:85126079057
VL - 19
JO - Journal of the Royal Society Interface
JF - Journal of the Royal Society Interface
SN - 1742-5689
IS - 188
M1 - 20220033
ER -