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This is mainly mediated <jats:italic>via<\/jats:italic> a translational control mechanism dependent upon the translation initiation eIF2\u00b7GTP\u00b7Met-tRNA<jats:sub>i<\/jats:sub>\n              <jats:sup>Met<\/jats:sup> ternary complex, and the four short upstream open reading frames (uORFs) in its 5' mRNA leader. These uORFs act to attenuate <jats:italic>GCN4<\/jats:italic> mRNA translation under normal conditions. During amino acid starvation, levels of ternary complex are reduced. This overcomes the <jats:italic>GCN4<\/jats:italic> translation attenuation effect via a scanning\/reinitiation control mechanism dependent upon uORF spacing.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results<\/jats:title>\n            <jats:p>Using published experimental data, we have developed and validated a probabilistic formulation of <jats:italic>GCN4<\/jats:italic> translation using the Chemical Master Equation (Model 1). Model 1 explains <jats:italic>GCN4<\/jats:italic> translation's nonlinear dependency upon uORF placements, and predicts that an as yet unidentified factor, which was proposed to regulate <jats:italic>GCN4<\/jats:italic> translation under some conditions, only has pronounced effects upon <jats:italic>GCN4<\/jats:italic> translation when intercistronic distances are unnaturally short. A simpler Model 2 that does not include this unidentified factor could well represent the regulation of a natural <jats:italic>GCN4<\/jats:italic> mRNA. Using parameter values optimised for this algebraic Model 2, we performed stochastic simulations by Gillespie algorithm to investigate the distribution of ribosomes in different sections of <jats:italic>GCN4<\/jats:italic> mRNA under distinct conditions. Our simulations demonstrated that ribosomal loading in the 5'-untranslated region is mainly determined by the ratio between the rates of 5'-initiation and ribosome scanning, but was not significantly affected by rate of ternary complex binding. Importantly, the translation rate for codons starved of cognate tRNAs is predicted to be the most significant contributor to the changes in ribosomal loading in the coding region under repressing and derepressing conditions.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions<\/jats:title>\n            <jats:p>Our integrated probabilistic Models 1 and 2 explained <jats:italic>GCN4<\/jats:italic> translation and helped to elucidate the role of a yet unidentified factor. The ensuing stochastic simulations evaluated different factors that may impact on the translation of <jats:italic>GCN4<\/jats:italic> mRNA, and integrated translation status with ribosomal density.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1186\/1752-0509-5-131","type":"journal-article","created":{"date-parts":[[2011,8,18]],"date-time":"2011-08-18T18:23:28Z","timestamp":1313691808000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Analysing GCN4 translational control in yeast by stochastic chemical kinetics modelling and simulation"],"prefix":"10.1186","volume":"5","author":[{"given":"Tao","family":"You","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ian","family":"Stansfield","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"M Carmen","family":"Romano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alistair JP","family":"Brown","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"George M","family":"Coghill","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2011,8,18]]},"reference":[{"issue":"13","key":"734_CR1","doi-asserted-by":"publisher","first-page":"4347","DOI":"10.1128\/MCB.21.13.4347-4368.2001","volume":"21","author":"K Natarajan","year":"2001","unstructured":"Natarajan K, Meyer MR, Jackson BM, Slade D, Roberts C, et al.: Transcriptional profiling shows that Gcn4p is a master regulator of gene expression during amino acid starvation in yeast. 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