Ribosome Protein Heterogeneity: The basis of wide spread roles for specialized ribosomes in tuning global gene expression.

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The traditional view of the ribosome is where each large and small ribosomal subunit is composed of its ribosomal RNAs and a defined set of ribosomal proteins. Now emerging evidence is beginning to challenge this view of a static universal ribosome structure as it is becoming apparent that different ribosomes can vary in their make-up of many core ribosomal proteins. Recent published data is also revealing the functional implications of variable ribosomal protein composition of ribosomes as there are examples demonstrating the requirement for specific ribosomal proteins for the translation of specific mRNAs. For example, recently published work describes how ribosomes containing Rpl38 are required for the translation of specific Hox genes in specific cells during development. One can envision numerous scenarios how specialized ribosomes which vary in their core ribosomal protein content are tuned for optimal gene expression in different cell types and tissues. ******Preliminary Data: Following up on previously published data that quantified large differences for some ribosomal protein mRNAs between different murine tissues, we have quantitatively compared the ribosomal proteome of purified ribosomes from some murine tissues and cell lines. Our preliminary data is in agreement with the mRNA expression data where we have also quantified highly variable abundances for several ribosomal proteins while others remain constant. This variability of a subset of ribosomal proteins merits further investigations into the functional implications in gene expression.******To further investigate ribosome variability we are pursuing the following Specific Aims:******Aim 1) Quantifying Ribosomal Variations: Complete our quantification of the differences in the ribosomal proteome of ribosomes purified from different murine tissues and cell lines. ******Aim 2) Functional Investigations of Ribosomal Variants: Identify the mRNAs being actively translated in polysomes in the murine 3T3 cell line in the presence and absence of ribosomal proteins that exhibit variable ribosomal occupancy. ******Aim 3) Mechanistic Investigations of Translational Evasion: Investigate the molecular basis of how these mRNAs under ribosomal specific selective translation are not translated by canonical 5'-cap dependent translation and require specific ribosomal proteins for translation.******Impact: The demonstration of the breadth of the role for ribosomes in gene expression by selective mRNA translation would redefine how we view the role of ribosomes in protein synthesis. The identification of ribosomes playing an active role in the regulation of gene expression may be one of the largest overlooked aspects of post transcriptional gene regulation and has the potential to function in numerous regulatory roles in both development and disease.