QKI shuttles internal m7G-modified transcripts into stress granules and modulates mRNA metabolism

N7-methylguanosine (m7G) modification, routinely occurring at mRNA 50 cap or within tRNAs/rRNAs, also ex-ists internally in messenger RNAs (mRNAs). Although m7G-cap is essential for pre-mRNA processing and protein synthesis, the exact role of mRNA internal m7G modification remains elusive. Here, we report that mRNA internal m7G is selectively recognized by Quaking proteins (QKIs). By transcriptome-wide profiling/ mapping of internal m7G methylome and QKI-binding sites, we identified more than 1,000 high-confidence m7G-modified and QKI-bound mRNA targets with a conserved GANGAN (N = A/C/U/G)motif. Strikingly, QKI7 interacts (via C terminus) with the stress granule (SG) core protein G3BP1 and shuttles internal m7G-modified transcripts into SGs to regulate mRNA stability and translation under stress conditions. Specifically, QKI7 attenuates the translation efficiency of essential genes in Hippo signaling pathways to sensitize cancer cells to chemotherapy. Collectively, we characterized QKIs as mRNA internal m7G-binding proteins that modulate target mRNA metabolism and cellular drug resistance.

Automated summary

The mRNA internal m7G modification is recognized by Quaking proteins (QKIs), which regulate mRNA stability and translation, affecting cellular drug resistance.