| Summary: | Myotonic dystrophy type 2 (DM2) is an autosomal dominant human disease caused by the expansion of a tetranucleotide repeat in the first intron of the ZNF9 gene. While multiple studies link nucleotide expansions such as those found in the ZNF9 gene to a variety of other human diseases, it is unclear whether the expanded repeat results in a misregulation of ZNF9. This work focuses on the molecular function of the ZNF9 protein and what role aberrant ZNF9 expression plays in DM2 pathology. ZNF9 activates cap-independent translation of ornithine decarboxylase (ODC) through a direct interaction with the 5 untranslated region of the ODC mRNA. This activity is reduced in myoblasts from DM2 patients, suggesting that nucleotide expansions at the DM2 locus result in a misregulation of the ZNF9 protein. An ortholog of ZNF9 in Saccharomyces cerevisiae, Gis2p, shows striking conservation in biochemical interactions and can activate translation of the ODC mRNA in mammalian systems, providing an alternative system for studying ZNF9 activity and function. Finally, mass spectrometry-based proteomic analysis of DM2 mouse models reveals that a large number of skeletal muscle regulatory proteins show aberrant expression as a result of a loss of ZNF9 activity. Together, this work provides evidence that ZNF9 acts as a regulator of the essential cellular process of translation and that DM2 may result due in part to defects in the expression or regulation of this protein.
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