Microprotein Regulates G-quadruplex Driven RNA Aggregation

Repeat expansions of the hexanucleotide GGGGCC in C9orf72 form aberrant phase transitions that have been linked to Amyotrophic Lateral Sclerosis and Frontotemporal Dementia. RNA structures such as G-quadruplexes and hairpins play important roles in these processes. Here, we show that the human microprotein ZNF706 acts as a modulator of G-quadruplex formation and RNA phase behavior. ZNF706 antagonizes pathological gel-solid transitions by melting hexanucleotide repeat G-quadruplex structures converting gel-like aggregates into more dynamic condensates. Loss of ZNF706 enhances the cellular production clearance of hexanucleotide repeat-mediated dipeptide repeat proteins, while overexpression suppresses their production and promotes clearance. Mechanistically, ZNF706 influences hexanucleotide repeat condensate fluidity and viscoelasticity. We find ZNF706 acts as an RNA chaperone that remodels repeat RNA structures and solubilizes RNA aggregates. This activity represents one mechanism whereby cells can regulate G-quadruplex driven phase transitions linked to neurodegenerative diseases.