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

Abstract

N⁷-methylguanosine (m⁷G) modification, routinely occurring at mRNA 5' cap or within tRNAs/rRNAs, also exists 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.