A DNA G-quadruplex converts SOD1 into fibrillar aggregates

Nucleic acids with G4 elements play a role in the formation of aggregates involved in intracellular phase transitions. Our previous studies suggest that different forms of DNA could act as an accelerating template in Cu/Zn superoxide dismutase (SOD1) aggregation. Here, we examined the regulation of formation and cytotoxicity of the SOD1 aggregates by single-stranded 12-mer deoxynucleotide oligomers (dN)₁₂ (N = A, T, G, C; ssDNAs) under acidic conditions. The ssDNAs can be divided into two groups based on their roles in SOD1 binding, exposure of hydrophobic clusters in SOD1, accelerated formation, morphology and cytotoxicity of SOD1 aggregates. G-quadruplexes convert SOD1 into fibrillar aggregates as a template, a fact which was observed for the first time in the nucleic acid regulation of protein aggregation. Moreover, the fibrillar or fibril-like SOD1 species with a G-quadruplex provided by (dG)₁₂ were less toxic than the amorphous species with (dN)₁₂ (N = A, T). This study not only indicates that both morphology and cytotoxicity of protein aggregates can be regulated by the protein-bound DNAs, but also help us understand roles of nucleic aid G-quadruplexes in the formation of aggregates and membraneless organelles involved in intracellular phase transitions.