Abstracts of Albany 2009: 16th Conversation. June 16-20 2009. Albany, New York, USA.

摘要

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 manifest by the observation that the process of mRNA degradation is intertwined with mRNA translation, exhibiting an inverse relationship. Specifically, alterations in the rate translational initiation lead to dramatic destabilization of mRNAs. Additionally, translational initiation defects can be suppressed by mutations a component of the mRNA decapping factor. Lastly, decapping is postulated to require dissociation of the mRNA from ribosomes and packaging into sub-cellular, ribosome-free granules termed P-bodies. These findings have lead to a well accepted model in which the cessation of mRNA translation and packaging into P-bodies 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 couple remains ambiguous. We will highlight our recent work focused on understanding the connection between mRNA decay and translation. We demonstrate that mRNA decapping and exonucleolytic decay occurs while mRNA is still engaged with ribosomes. Specifically, the substrate for decapping, deadenylated mRNA, is found associated with ribosomes. Moreover, decapped mRNA can be detected bound to polyribosomes indicating deadenylation and decapping occurs concurrently with translation. Additionally, we show that products of 5' exonucleolytic degradation are polyribosome associated. These data demonstrate that removal of mRNA from ribosomes is not a prerequisite for degradation and that mRNA decapping and 5'-3' decay occur co-translationally under normal conditions. Considering this finding, we propose the polarity of mRNA decay (i.e., decapping and 5'-3' decay) has evolved to ensure degradation does not impede the last translocating ribosome.