Small molecule kinase inhibitors alleviate different molecular features of myotonic dystrophy type 1.
Expandable (CTG)n repeats in the 3' UTR of the DMPK gene are a cause of myotonic dystrophy type 1 (DM1), which leads to a toxic RNA gain-of-function disease. Mutant RNAs with expanded CUG repeats are retained in the nucleus and aggregate in discrete inclusions. These foci sequester splicing factors of the MBNL family and trigger upregulation of the CUGBP family of proteins resulting in the mis-splicing of their target transcripts. To date, many efforts to develop novel therapeutic strategies have been focused on disrupting the toxic nuclear foci and correcting aberrant alternative splicing via targeting mutant CUG repeats RNA; however, no effective treatment for DM1 is currently available. Herein, we present results of culturing of human DM1 myoblasts and fibroblasts with two small-molecule ATP-binding site-specific kinase inhibitors, C16 and C51, which resulted in the alleviation of the dominant-negative effects of CUG repeat expansion. Reversal of the DM1 molecular phenotype includes a reduction of the size and number of foci containing expanded CUG repeat transcripts, decreased steady-state levels of CUGBP1 protein, and consequent improvement of the aberrant alternative splicing of several pre-mRNAs misregulated in DM1.
Department of Molecular Biomedicine; Institute of Bioorganic Chemistry; Polish Academy of Sciences; Noskowskiego; Poznan, Poland.
Marzena
M
Wojciechowska
Department of Gene Expression; Institute of Molecular Biology and Biotechnology; Adam Mickiewicz University; Umultowska 89; Poznan, Poland.
Katarzyna
K
Taylor
Department of Gene Expression; Institute of Molecular Biology and Biotechnology; Adam Mickiewicz University; Umultowska 89; Poznan, Poland.
Krzysztof
K
Sobczak
Department of Biochemistry and Molecular Genetics and UAB Stem Cell Institute; University of Alabama at Birmingham; Birmingham, AL USA.
Marek
M
Napierala
Department of Molecular Biomedicine; Institute of Bioorganic Chemistry; Polish Academy of Sciences; Noskowskiego; Poznan, Poland.
Wlodzimierz J
WJ
Krzyzosiak
D017398:Alternative Splicing; D000067879:CELF1 Protein; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects; D006801:Humans; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism; D009223:Myotonic Dystrophy / Q000188:drug therapy / Q000201:enzymology / Q000235:genetics*; D010770:Phosphotransferases / Q000037:antagonists & inhibitors*; D011485:Protein Binding / Q000187:drug effects; D021381:Protein Transport / Q000187:drug effects; D012322:RNA Precursors; D012326:RNA Splicing; D012333:RNA, Messenger; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic
D000067879:CELF1 Protein; C102843:CELF1 protein, human; D004791:Enzyme Inhibitors; C493663:MBNL1 protein, human; D012322:RNA Precursors; D012333:RNA, Messenger; D016601:RNA-Binding Proteins; D010770:Phosphotransferases
CUG Foci; CUGBP1 protein; MBNL1 protein; RNA splicing; RNA-binding proteins; myotonic dystrophy; protein kinases; protein phosphorylation