Speaker: Dirk de Vos (CWI)

Title: Towards solving the paradox of gene expression: modelling translation regulation in Saccharomyces cerevisiae

Date: Thursday 19 March (13.00-14.00h)

Location: CWI, room M279

ABSTRACT
Translation, or protein synthesis, is a process that is central to cellular function. It is one of the processes in the "central dogma" of molecular biology, which states that DNA encodes mRNA and mRNA encodes proteins. However, paradoxically, mRNA concentrations turn out to correlate poorly with protein concentrations, even in steady-state chemostat cultures. The most plausible explanation for this finding is that much regulation of gene expression is posttranscriptional. Indeed, regulatory mechanisms that affect translation, protein degradation, posttranslational modification of proteins have been documented extensively. High-throughput measurements of translation rates and protein turn-over in Saccharomyces cerevisiae showed that these varied significantly between proteins and conditions. Moreover, in a recent study it was shown that protein synthesis or degradation contributed 75-100% of the regulation of glycolytic enzyme levels when chemostat cultured S. cerevisiae was confronted with the absence of oxygen. To investigate the mechanisms of translation regulation underlying the observed lack of correlation, a dynamic model was built of the 'translational machinery' of S. cerevisiae. This model captures the interplay between the initiation, elongation and termination phases of different mRNAs. Interestingly, our analysis shows that the competition of multiple mRNA species for a common pool of ribosomes has important regulatory implications. A framework is proposed which allows this 'cross-talk' between mRNAs to be quantified, in terms of response coefficients, based on the formalism of Metabolic Control Analysis. It furthermore demonstrates that 'indirect' regulation through system-wide competition potentially can have significant impact on the way we understand and interpret the relationship between mRNA and protein expression.