Journal
NUCLEIC ACIDS RESEARCH
Volume 43, Issue 20, Pages 10055-+Publisher
OXFORD UNIV PRESS
DOI: 10.1093/nar/gkv1008
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Funding
- Weston Brain Institute
- Amyotrophic Lateral Sclerosis Association of America
- Natural Science and Engineering Research Council of Canada
- National Institutes of Health [R01 DK083310, R21 GM111439, R33 CA191135]
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Unusual DNA/RNA structures of the C9orf72 repeat may participate in repeat expansions or pathogenesis of amyotrophic lateral sclerosis and frontotemporal dementia. Expanded repeats are CpG methylated with unknown consequences. Typically, quadruplex structures form by G-rich but not complementary C-rich strands. Using CD, UV and electrophoresis, we characterized the structures formed by (GGGGCC) 8 and (GGCCCC)8 strands with and without 5-methylcytosine (5mCpG) or 5-hydroxymethylcytosine (5hmCpG) methylation. All strands formed heterogenous mixtures of structures, with features of quadruplexes (at pH 7.5, in K+, Na+ or Li+), but no feature typical of i-motifs. C-rich strands formed quadruplexes, likely stabilized by G center dot C center dot G center dot C-tetrads and C center dot C center dot C center dot C-tetrads. Unlike G center dot G center dot G center dot G-tetrads, some G center dot C center dot G center dot C-tetrad conformations do not require the N7-Guanine position, hence C9orf72 quadruplexes still formed when N7-deazaGuanine replace all Guanines. 5mCpG and 5hmCpG increased and decreased the thermal stability of these structures. hnRNPK, through band-shift analysis, bound C-rich but not G-rich strands, with a binding preference of unmethylated > 5hmCpG > 5mCpG, where methylated DNA-protein complexes were retained in the wells, distinct from unmethylated complexes. Our findings suggest that for C-rich sequences interspersed with G-residues, one must consider quadruplex formation and that methylation of quadruplexes may affect epigenetic processes.
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