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

  • Cell. 2023 Jul 20;186(15):3208-3226.e27. doi: 10.1016/j.cell.2023.05.047.
Zhicong Zhao  1 ,  Ying Qing  2 ,  Lei Dong  2 ,  Li Han  3 ,  Dong Wu  2 ,  Yangchan Li  4 ,  Wei Li  2 ,  Jianhuang Xue  5 ,  Keren Zhou  2 ,  Miao Sun  6 ,  Brandon Tan  2 ,  Zhenhua Chen  2 ,  Chao Shen  2 ,  Lei Gao  2 ,  Andrew Small  2 ,  Kitty Wang  2 ,  Keith Leung  2 ,  Zheng Zhang  2 ,  Xi Qin  2 ,  Xiaolan Deng  2 ,  Qiang Xia  7 ,  Rui Su  8 ,  Jianjun Chen  9
Affiliations
  • 1. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China.
  • 2. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA.
  • 3. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; School of Pharmacy, China Medical University, Shenyang, Liaoning 110001, China.
  • 4. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Department of Radiation Oncology, The First Affiliated Hospital of Sun Yat-sen University, Guangzhou, Guangdong 510080, China.
  • 5. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; Key Laboratory of Spine and Spinal Cord Injury Repair and Regeneration of Ministry of Education, Tongji Hospital affiliated to Tongji University, Shanghai 200065, China; Frontier Science Center for Stem Cell Research, School of Life Sciences and Technology, Tongji University, Shanghai 200092, China.
  • 6. Keck School of Medicine, University of Southern California, and Department of Pathology and Laboratory Medicine, Children's Hospital Los Angeles, Los Angeles, CA 90027, USA.
  • 7. Department of Liver Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai 200127, China. Electronic address: [email protected].
  • 8. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: [email protected].
  • 9. Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA; City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA 91010, USA. Electronic address: [email protected].
PMID: 37379838 DOI: 10.1016/j.cell.2023.05.047
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.

Keywords
G3BP1; METTL1; N(7)-methylguanosine; QKI; drug resistance; m(7)G; mRNA metabolism; mRNA stability; stress granule; translational regulation.