TMPyP4 Distorts RNA G-Quadruplex Structures of the Disease-Associated r(GGGGCC)n Repeat of the C9orf72 Gene and Blocks Interaction of RNA-Binding Proteins [Molecular Bases of Disease]

December 26th, 2013 by Zamiri, B., Reddy, K., Macgregor, R. B., Pearson, C. E.

Certain DNA and RNA sequences can form G-quadruplexes, which can affect genetic instability, promoter activity, RNA splicing, RNA stability, and neurite mRNA localization. Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) can be caused by expansion of a (GGGGCC)n repeat in the C9orf72 gene. Mutant r(GGGGCC)n- and r(GGCCCC)n-containing transcripts aggregate in nuclear foci possibly sequestering repeat-binding proteins like ASF/SF2 and hnRNPA1 suggesting a toxic RNA pathogenesis, as occurs in myotonic dystrophy. Furthermore, the C9orf72 repeat RNA was recently demonstrated to undergo the non-canonical repeat associated non-AUG translation (RAN-translation) into pathologic dipeptide repeats in patient brains, a process that is thought to depend upon RNA structure. We previously demonstrated that the r(GGGGCC)n RNA forms repeat tract length-dependent G-quadruplex structures that bind by the ASF/SF2 protein. Here we show that the cationic porphyrin (TMPyP4), which can bind some G-quadruplex forming sequences, can bind and distort the G-quadruplex formed by r(GGGGCC)8, and this ablates the interaction of either hnRNPA1 or ASF/SF2 with the repeat. These findings provide proof-of-concept that nucleic acid binding small molecules, like TMPyP4, can distort the secondary structure of the C9orf72 repeat, which may beneficially disrupt protein interactions, which may ablate either protein-sequestration and/or RAN-translation into potentially toxic dipeptides. Disruption of secondary structure formation of the C9orf72 RNA repeats may be a viable therapeutic avenue, as well as a means to test the role of RNA structure upon RAN-translation.
  • Posted in Journal of Biological Chemistry, Publications
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