Translational control by 5'-UTR elements

University Of Michigan At Ann Arbor, Ann Arbor MI

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Abstract

Aberrant protein synthesis is associated with a variety of disease states such as cancer and neurodegeneration. The protein output per mRNA is strongly affected by a combination of cis elements and trans factors that together control the rate of recruitment of ribosomes to the 5′-untranslated region (5′-UTR). Different 5′-UTRs are sufficient to confer a thousand-fold range of translation output both in vivo and in vitro, but the mechanisms underlying these large effects are unknown in most cases. This R00 Pathway to Independence Award seeks to understand the 5′-UTR regulatory code controlling mRNA translation by answering two fundamental questions: (1) what are the components of the code? And (2) what is the mechanism by which the components affect translational activity? To answer these questions Dr. Niederer will take advantage of a cellular condition where widespread changes in 5′-UTR usage have been observed- cancer. During the K99 phase, Dr. Niederer Used a novel technical approach to directly measure ribosome recruitment levels to thousands of differentially expressed 5′-UTR sequences (previous Aim 1). While the changes in 5′-UTR usage are well known, their effect on ribosome recruitment is more or less completely unknown. In this R00 phase, Dr. Niederer will use a combination of biochemical and genetic studies to identify the readers of these functional RNA elements (new Aim 1). This work will be extended by the efforts of Cesar Martinez, who will be performing mutagenesis to delineate the functional boundaries of the identified elements. This will be critical for identifying candidate readers that are specific to the newly identified translational repressors and enhancers. Dr. Niederer will then characterize the candidate readers and determine their role in supporting translational reprogramming in cells exposed to oncogenic insults or undergoing stress response. Additional work will measure ribosome recruitment to additional 5′-UTRs of interest, including those (1) containing pathogenic SNPs and (2) exhibiting tissue specific expression (new Aim 2). The results of this work are likely to reveal novel mechanisms of translation regulation, which will not only further our understanding of a fundamental cellular process but will also have implications for human health and disease.