A mathematical modelling framework for elucidating the role of feedback control in translation termination

Abstract

Translation is the final stage of gene expression where messenger RNA is used as a template for protein polymerisation from appropriate amino acids. Release of the completed protein requires a release factor protein acting at the termination/stop codon to liberate it. In this paper we focus on a complex feedback control mechanism involved in the translation and synthesis of release factor proteins, which has been observed in different systems. These release factor proteins are involved in the termination stage of their own translation. Further, mutations in the release factor gene can result in a premature stop codon. In this case translation can result either in early termination and the production of a truncated protein or readthrough of the premature stop codon and production of the complete release factor protein. Thus during translation of the release factor mRNA containing a premature stop codon, the full length protein negatively regulates its production by its action on a premature stop codon, while positively regulating its production by its action on the regular stop codon. This paper develops a mathematical modelling framework to investigate this complex feedback control system involved in translation. A series of models is established to carefully investigate the role of individual mechanisms and how they work together. The steady state and dynamic behaviour of the resulting models are examined both analytically and numerically.

Mathematical and Computational Modelling of Ribosomal Movement and Protein Synthesis: An Overview

“…Although this approach is sometimes used to model the actual movement of ribosomes on mRNAs [50–53], it suffers from the same difficulties as outlined above for analytical models of translation regarding the size of equation systems that can result from describing each possible codon:ribosome complex as an individual species. However, numerical approximations have been the main approach for modelling the sub-processes of translation initiation [54–57] and termination [58]. …”

“…Thus, Godefroy-Colburn and Thach described initiation via five sub-reactions [20], Heyd and Drew dissected the elongation step into seven sub-reactions [51], and de Silva et al . presented several fine-grained descriptions of the termination step [58]. All of these models analysed the full ribosome cycle.…”

Autoregulatory systems controlling translation factor expression: Thermostat-like control of translational accuracy

“…This approach will enable a quantitative examination of the termination process, its interplay with the competing tRNA population, and the role of cis factors such as stop codon context and frameshifting (de Silva et al 2010). …”

Regulation of release factor expression using a translational negative feedback loop: A systems analysis

“…eRF1 nonsense mutations of this type have been isolated in the presence of specific mutant suppressor tRNAs that help support readthrough of the premature stop codon (Stansfield et al 1996), but intriguingly, also in wild-type tRNA backgrounds (Moskalenko et al 2003). The level of readthrough of the premature eRF1 nonsense codons is regulated by a complex interaction between the suppressor tRNA efficiency (Stansfield et al 1996;de Silva et al 2010), the eRF1 protein stability and activity, and the modulatory effect of the nonsense-mediated mRNA decay system that acts to destabilize mRNAs carrying early stop codons (Chabelskaya et al 2007;Kiktev et al 2009). As in the case of the RF2 feedback loop, this system appears to be autoregulatory.…”