Investigating the potential role of CDK13 in the transcription and stability of mutant DMPK mRNA in myotonic dystrophy type 1
Publication Date
July 27, 2026
Creator
Brown, Jessie
Abstract
Myotonic Dystrophy (DM) is a complex multisystemic genetic disorder characterised by muscular dystrophy, myotonia and cardiorespiratory abnormalities. DM is classified as a repeat expansion disorder. DM type 1 is caused by a trinucleotide repeat expansion of CTG in the 3’untranslated region of the dystrophia myotonica protein kinase gene (DMPK). The mutant expansion RNA has a gain of function mechanism whereby the RNA is primarily retained in the nucleus and sequesters the RNA binding protein, muscle blind-like 1 (MBNL1) to form nuclear RNA foci. Cyclin dependent kinases 12 and 13 (CDK12/13) are transcriptional kinases which promote and maintain RNA polymerase II transcriptional elongation and processivity. Knockdown of either kinase has been shown to negatively impact transcription, DNA repair mechanisms and cell viability with greater effects seen upon dual knockdown. CDK12 and CDK13 share a large degree of functional redundancy but each have their own specific roles and regulate their own subset of genes. CDK12 Knockdown has been shown in human DM1 cell lines and mouse models to reduce nuclear RNA foci and improve myotonia. In this project I have examined whether CDK13 knockdown results in reduced abundance, size and intensity of nuclear RNA foci like its ortholog CDK12. To examine this, I have performed transductions using shRNA containing lentiviruses, western blotting and fluorescence in-situ hybridisation. This project has also looked at CDK13 half-life using cycloheximide as well as using online databases to analyse CDK13 and CDK12 expression in mouse and human DM1 patient tissues. This project found CDK13 to be present in human DM1 fibroblast cell lines, but it could not be detected in mouse brain, heart or muscle tissue samples. A 30% reduction in CDK13 resulted in visible but not statistically significant decreases in RNA foci abundance and area, but did result in a significant decrease in RNA foci intensity. This project also reports that the half-life of CDK13 in the DM1 KB cell line to be 6.13 hours (95% CI [3.02, 29.11]). The findings here provide preliminary evidence to suggest that CDK13 may behave like CDK12 in the context of DM1 and influence RNA foci dynamics, however, more experiments are required and will involve reducing CDK13 levels further as well as including more technical and biological replicates.
Item Type
ethesis
Thesis Type
MRes
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Subjects (LC)
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