(C2G4)n Repeat Expansion Sequences from the C9orf72 Gene Form an Unusual DNA Higher-Order Structure in the pH Range of 5-6

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Lat PK, Sen D (2018) (C2G4)n repeat expansion sequences from the C9orf72 gene form an unusual DNA higher-order structure in the pH range of 5-6. PLoS ONE 13(6): e0198418. DOI: 10.1371/journal.pone.0198418.

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Massive expansion of a DNA hexanucleotide sequence repeat (C2G4) within the human C9orf72 gene has been linked to a number of neurodegenerative diseases. In sodium or potassium salt solutions, single-stranded d(C2G4)n DNAs fold to form G-quadruplexes. We have found that in magnesium or lithium salt solutions, especially under slightly acidic conditions, d(C2G4)n oligonucleotides fold to form a distinctive higher order structure whose most striking feature is an “inverted” circular dichroism spectrum, which is distinguishable from the spectrum of the left handed DNA double-helix, Z-DNA. On the basis of CD spectroscopy, gel mobility as well as chemical protection analysis, we propose that this structure, which we call “iCD-DNA”, may be a left-handed Hoogsteen base-paired duplex, an unorthodox G-quadruplex/i-motif composite, or a non-canonical, “braided” DNA triplex. Given that iCD-DNA forms under slightly acidic solution conditions, we do not know at this point in time whether or not it forms within living cells.

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Natural Sciences and Engineering Research Council of Canada (NSERC)