G‐Quadruplexes act as sequence‐dependent protein chaperones

Maintaining proteome health is important for cell survival. Nucleic acids possess the ability to prevent protein aggregation more efficiently than traditional chaperone proteins. In this study, we explore the sequence specificity of the chaperone activity of nucleic acids. Evaluating over 500 nucleic acid sequences’ effects on protein aggregation, we show that the holdase chaperone effect of nucleic acids is sequence‐dependent. G‐Quadruplexes prevent protein aggregation via quadruplex:protein oligomerization. They also increase the folded protein level of a biosensor in E. coli. These observations contextualize recent reports of quadruplexes playing important roles in aggregation‐related diseases, such as fragile X and amyotrophic lateral sclerosis (ALS), and provide evidence that nucleic acids have the ability to modulate the folding environment of E. coli.