RRM
2007Rustbelt RNA Meeting
RRM
|
|
|
|
|
Talk abstracts
Abstract:
The regulated turnover of mRNA is recognized as a vital aspect of gene expression. The importance of maintaining appropriate mRNA decay is exemplified by the complexity of the decay process; there are three distinct steps (deadenylation, decapping, and exonucleolytic decay) and over 20 protein factors are involved. An additional layer of complexity is manifested by the observation that the process of mRNA degradation is intertwined with mRNA translation, exhibiting an inverse relationship. Specifically, decrease in the rate translational initiation lead to dramatic destabilization of mRNAs. Additionally, translational initiation defects can be suppressed by mutations of a component of the mRNA decapping factor. Conversely, inhibition of mRNA translation elongation, either in cis or in trans, results in a dramatic stabilization of mRNAs. This has lead to a well accepted model in which the cessation of mRNA translation is thought to be an initial and necessary step in the regulated destruction of cytoplasmic mRNA transcripts. Despite these long-standing observations, the precise and detailed mechanism of how mRNA translation and mRNA decay are coupled remains ambiguous.
Our work focuses on dissecting the complex interconnectivity between mRNA decay and mRNA translation. Recent data have pointed to the observation that mRNA decay specifically impacts the process of translational elongation. First, we find that mutation in factors involved in the second step of mRNA decay, i.e. the decapping reaction, are extraordinarily sensitivity to drugs that inhibit the process of translational elongation. Consistent with this, mRNAs accumulate with an abnormally large number of bound ribosomes in decapping mutants when compared to wild-type cells. These results suggest that the rate of translation elongation is slowed in these mutants. Consistent with this, direct measurement of the ribosome transit time in decapping mutants reveals that translation elongation is compromised when decapping does not occur appropriately. We are currently in the process of determining how decapping of mRNA is connected to translational elongation, but believe, however, that investigation into this newly recognized step of gene regulation will have significant impact on our overall comprehension of the relationship between mRNA translation and turn-over and in understanding the regulation of gene expression in a variety of biological contexts.
Keywords: mRNA turnover, translation elongation, decapping
