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

Zhicong Zhao; Ying Qing; Lei Dong; Li Han; Dong Wu; Yangchan Li; Wei Li; Jianhuang Xue; Keren Zhou; Miao Sun; Brandon Tan; Zhenhua Chen; Chao Shen; Lei Gao; Andrew Small; Kitty Wang; Keith Leung; Zheng Zhang; Xi Qin; Xiaolan Deng; Qiang Xia; Rui Su; Jianjun Chen

doi:10.1016/j.cell.2023.05.047

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. Epub 2023 Jun 27.

Authors

Zhicong Zhao¹, Ying Qing², Lei Dong², Li Han³, Dong Wu², Yangchan Li⁴, Wei Li², Jianhuang Xue⁵, Keren Zhou², Miao Sun⁶, Brandon Tan², Zhenhua Chen², Chao Shen², Lei Gao², Andrew Small², Kitty Wang², Keith Leung², Zheng Zhang², Xi Qin², Xiaolan Deng², Qiang Xia⁷, Rui Su⁸, Jianjun Chen⁹

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: xiaqiang@shsmu.edu.cn.
⁸ Department of Systems Biology, Beckman Research Institute of City of Hope, Monrovia, CA 91016, USA. Electronic address: rsu@coh.org.
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: jianchen@coh.org.

PMID: 37379838
PMCID: PMC10527483 (available on 2024-07-20)
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.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Cytoplasmic Granules / metabolism
DNA Helicases* / metabolism
GTP-Binding Proteins / metabolism
Poly-ADP-Ribose Binding Proteins / genetics
Poly-ADP-Ribose Binding Proteins / metabolism
RNA Helicases* / metabolism
RNA Recognition Motif Proteins / genetics
RNA Recognition Motif Proteins / metabolism
RNA, Messenger / metabolism
Stress Granules

Substances

DNA Helicases
RNA Recognition Motif Proteins
RNA Helicases
Poly-ADP-Ribose Binding Proteins
GTP-Binding Proteins
RNA, Messenger

Abstract

Publication types

MeSH terms

Substances

Grants and funding