The major biological form of selenium is the amino acid selenocysteine which is specifically incorporated into the active site of selenoproteins. These constitute a family of oxidation-reduction enzymes involved in a variety of well-established important functions, such as reduction of reactive oxygen species, thyroid hormone maturation, sperm maturation and muscle development. Selenocysteine sets apart from the other amino acids because of its peculiar biosynthesis pathway and incorporation into selenoproteins in response to a reprogrammed UGA codon. A complex machinery, comprising at least eight specialized gene products, participate in this process. For selenoprotein synthesis, the essential components are the SECIS element, an RNA stem-loop structure in the 3' untranslated region of selenoprotein mRNAs, and the SECIS-binding protein SBP2. We identified the SBP2 amino acids and SECIS nucleotides important for SBP2-SECIS RNA complex formation. Besides, and very unexpectedly, we discovered that the assembly and maturation of selenoprotein mRNAs into mRNPs (RNP stands for RiboNucleoproteinParticle) share several characteristic features and molecular components with that of small nuclear RNPs (involved in pre-mRNA splicing) and small nucleolar RNPs (participating in ribosomal RNA maturation), in particular the necessity of the Hsp90 chaperone.
Patients carrying mutations in the selenoprotein N gene (a protein discovered in my laboratory) develop congenital muscular dystrophies. We found that the protein resides in the endoplasmic reticulum and is highly expressed at early stages of embryonic development. In an attempt for a gene correction strategy, we successfully established an ex vivo approach to restore expression of a full-length selenoprotein N in cultured patient-derived skin fibroblasts.
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