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Translation initiation and assembly of selenoproteins mRNAs

Translation initiation in eukaryotes is a complex mechanism involving multiple factors and several successive steps. The team is studying the initiation mechanisms of mRNAs encoding selenoproteins as well as the assembly of these mRNAs

Selenoproteins play an essential role in the antioxidizing protection and the preservation of the redox potential of the cells. In Homo sapiens, 25 selenoproteins are involved in diverse fundamental mechanisms. Among these, glutathion peroxydases (GpX) and thioredoxin reductase (TrxR) play critical roles for keeping the cellular redox potential. The loss of function of these enzymes is associated with a strong risk of cancer. Understanding their mode of regulation and expression presents a special therapeutic interest.

Selenium is incorporated into selenoproteins as selenocystein (Sec). Sec is coded by a codon UGASec usually ending translation but redefined not to stop through a complex recoding mechanism not yet fully understood. In eukaryotes, the process involves factors binding to the 3’ untranslated region of selenoprotein mRNAs. A stem-loop structure called SECIS element (SElenoCystein Insertion Sequence) is specifically recognized by protein SBP2 to recruit factors of the translation machinery. We showed that the assembly of selenoprotein mRNAs exhibits striking similarity with that of the other essential ribonucleoparticules (RNPs) of the cell.

Selenoprotein mRNA translational recoding

Recently, we characterized a new mechanism of maturation of the 5’-end cap of sélénoprotéine mRNAs (Wurth et al., 2014). Typically, eukaryotic mRNAs harbour monomethylated cap at their 5’ end (m7G). In the cell, the 5’-cap has multiple functions and is involved in processing, translation and degradation. We showed that several selenoprotein mRNAs exhibit a trimethylated cap (m32,2,7G) similar to the cap of small nucle(ol)ar RNAs (sn- and snoRNAs), which prevent their binding to initiation factor eIF4E. The trimethylated cap is synthesized by trimethylguanosine synthase 1 (Tgs1) that interacts with the mRNAs thanks to a complex of chaperones and core proteins also involved in sn- and sno ribonucleoparticules maturation. Our study also showed that the hypermethylated-capped selenoprotein mRNAs are associated with polysomes into the cytoplasm, suggesting that they are actively translated. We further showed that the activity of Tgs1, but not of eIF4E, is required for the synthesis of the GPx1 selenoprotein in vivo (Wurth et al., 2014).