Systematic profiling of cytosolic membraneless organelles reveals enrichment of oncogenic mRNA upon oxidative stress

Cytosolic mRNA regulation during and after stress is driven by distinct membraneless organelles. However, their compositional and functional dynamics throughout the stress response remain unclear. We combine APEX2-mediated proximity labeling, RNA sequencing, and high-content imaging to map the human P-body and stress granule transcriptomes during oxidative stress and recovery. Our findings reveal that P-bodies undergo extensive compositional remodeling during stress and that these changes persist during stress recovery. P-body-associated mRNAs during stress exhibit increased AU-rich elements and oncogenic content relative to the cytosol. In contrast, stress granule-associated mRNAs closely resemble the cytosol. These results uncover critical differences between P-bodies and stress granules, shedding light on their functional specialization. Our study provides a valuable resource of cytosolic membraneless organelle-associated transcripts and suggests a specialized role for P-bodies in stress adaptation and recovery.