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Systems level understanding of selenoprotein biosynthesis


Selenium (Se) is a trace element with roles in processes, such as brain function, male reproduction, and immune function. In mammals, Se is an essential element due to its presence in proteins in the form of selenocysteine (Sec) residue. Sec is known as the 21st amino acid in the genetic code and is co-translationally inserted into proteins in response to UGA codons, in competition with termination of protein synthesis. Mutations and single nucleotide polymorphisms in several selenoprotein genes have been associated with disease. We previously developed tools that allow efficient identification of selenoprotein genes. Using these tools, we identified sets of human and mouse selenoproteins (selenoproteomes). We further developed approaches that support integrative analyses of Se, Sec, and selenoprotein synthesis, most notably ribosome profiling. We are poised to benefit from this foundation by addressing critical questions in the field. First, we will characterize the impact of competition between Sec insertion and termination of protein synthesis. Sec insertion at UGA codons competes with termination, suggesting that large amounts of truncated proteins are synthesized and then must be degraded by the cells. This is further exacerbated by differences in Se metabolism among organs. We will utilize ribosome profiling to characterize selenoprotein synthesis in various organs of mice, define selenoprotein isoforms, and characterize the fate of truncated selenoproteins. Second, we will determine the rates and features of selenoprotein synthesis in various organs in a selenoprotein-, tissue-, and selenium diet-specific manner. Using ribosome profiling in live animals, we will determine the rates of selenoprotein synthesis at the level of organs and individual selenoproteins, characterize regulation of selenoprotein synthesis by dietary selenium, and examine parallel regulation of selenoprotein expression at the level of transcript abundance and selenoprotein synthesis in mouse organs.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.