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. Author manuscript; available in PMC: 2014 Sep 13.
Published in final edited form as: Nature. 2014 Mar 5;507(7491):195–200. doi: 10.1038/nature13124

Figure 5. A model for the molecular cascade resulting from the C9orf72 HRE structural polymorphism.

Figure 5

The DNA and RNA•DNA structures formed in the GGGGCC repeat region impede RNA polymerase transcription, which results in transcriptional pausing and abortion. This leads to a loss of full-length products and an accumulation of abortive transcripts. Abortive transcripts that contain the hexanucleotide repeats form G-quadruplexes and hairpins and bind essential proteins in a conformation-dependent manner. Sequestration of these proteins leads to nucleolar stress and other downstream defects. The repeat-containing transcripts can also escape the nucleus and be bound by ribosomal complexes, thereby increasing repeat-associated non-ATG-dependent translation that results in aggregative polydipeptides.