2017 journal article

Structure and Dynamics of DNA and RNA Double Helices Obtained from the GGGGCC and CCCCGG Hexanucleotide Repeats That Are the Hallmark of C9FTD/ALS Diseases


author keywords: Nucleotide repeat disorder; hexanucleotide repeat; C-C and G-G mismatches; C9FTD; ALS; e-motif
Source: Web Of Science
Added: August 6, 2018

A (GGGGCC) hexanucleotide repeat (HR) expansion in the C9ORF72 gene, and its associated antisense (CCCCGG) expansion, are considered the major cause behind frontotemporal dementia and amyotrophic lateral sclerosis. We have performed molecular dynamics simulations to characterize the conformation and dynamics of the 12 duplexes that result from the three different reading frames in sense and antisense HRs for both DNA and RNA. These duplexes display atypical structures relevant not only for a molecular level understanding of these diseases but also for enlarging the repertoire of nucleic-acid structural motifs. G-rich helices share common features. The inner G-G mismatches stay inside the helix in Gsyn-Ganti conformations and form two hydrogen bonds (HBs) between the Watson-Crick edge of Ganti and the Hoogsteen edge of Gsyn. In addition, Gsyn in RNA forms a base-phosphate HB. Inner G-G mismatches cause local unwinding of the helix. G-rich double helices are more stable than C-rich helices due to better stacking and HBs of G-G mismatches. C-rich helix conformations vary wildly. C mismatches flip out of the helix in DNA but not in RNA. Least (most) stable C-rich RNA and DNA helices have single (double) mismatches separated by two (four) Watson-Crick basepairs. The most stable DNA structure displays an "e-motif" where mismatched bases flip toward the minor groove and point in the 5' direction. There are two RNA conformations, where the orientation and HB pattern of the mismatches is coupled to bending of the helix.