Supramolecular Polymorphism of (G4C2)n Repeats Associated with ALS and FTD

Guanine-rich DNA sequences self-assemble into highly stable fourfold structures known as DNA-quadruplexes (or G-quadruplexes). G-quadruplexes have furthermore the tendency to associate into one-dimensional supramolecular aggregates termed G-wires. We studied the formation of G-wires in solutions of the sequences d(G(4)C(2))(n) with n = 1, 2, and 4. The d(G(4)C(2))(n) repeats, which are associated with some fatal neurological disorders, especially amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD), represent a challenging research topic due to their extensive structural polymorphism. We used dynamic light scattering (DLS) to measure translational diffusion coefficients and consequently resolve the length of the larger aggregates formed in solution. We found that all three sequences assemble into longer structures than previously reported. The d(G(4)C(2)) formed extremely long G-wires with lengths beyond 80 nm. The d(G(4)C(2))(2) formed a relatively short stacked dimeric quadruplex, while d(G(4)C(2))(4) formed multimers corresponding to seven stacked intramolecular quadruplexes. Profound differences between the multimerization properties of the investigated sequences were also confirmed by the AFM imaging of surface films. We propose that pi-pi stacking of the basic G-quadruplex units plays a vital role in the multimerization mechanism, which might be relevant for transformation from the regular medium-length to disease-related long d(G(4)C(2))(n) repeats.

Automated summary

Guanine-rich DNA sequences can self-assemble into stable fourfold structures known as DNA-quadruplexes, which can further aggregate into one-dimensional supramolecular structures called G-wires. The study investigated the formation of G-wires in solutions of d(G(4)C(2))(n) sequences and found that all three sequences formed longer structures than previously reported, with d(G(4)C(2)) producing extremely long G-wires. The multimerization properties and mechanisms of these sequences were revealed to play a crucial role in the transformation to disease-related long repeats.