RNA G-quadruplex organizes stress granule assembly through DNAPTP6 in neurons

Consecutive guanine RNA sequences can adopt quadruple-stranded structures, termed RNA G-quadruplexes (rG4s). Although rG4-forming sequences are abundant in transcriptomes, the physiological roles of rG4s in the central nervous system remain poorly understood. In the present study, proteomics analysis of the mouse forebrain identified DNAPTP6 as an RNA binding protein with high affinity and selectivity for rG4s. We found that DNAPTP6 coordinates the assembly of stress granules (SGs), cellular phase-separated compart-ments, in an rG4-dependent manner. In neurons, the knockdown of DNAPTP6 diminishes the SG formation under oxidative stress, leading to synaptic dysfunction and neuronal cell death. rG4s recruit their mRNAs into SGs through DNAPTP6, promoting RNA self-assembly and DNAPTP6 phase separation. Together, we propose that the rG4-dependent phase separation of DNAPTP6 plays a critical role in neuronal function through SG assembly.

Automated summary

In this study, DNAPTP6 was identified as an RNA binding protein that plays a critical role in coordinating the assembly of stress granules (SGs) in a rG4-dependent manner. The recruitment of mRNAs into SGs through DNAPTP6 promotes RNA self-assembly and DNAPTP6 phase separation, which is essential for neuronal function.