IGF2BP3 promotes mRNA degradation through internal m7G modification

Chang Liu; Xiaoyang Dou; Yutao Zhao; Linda Zhang; Lisheng Zhang; Qing Dai; Jun Liu; Tong Wu; Yu Xiao; Chuan He

doi:10.1038/s41467-024-51634-w

IGF2BP3 promotes mRNA degradation through internal m⁷G modification

Nat Commun. 2024 Aug 28;15(1):7421. doi: 10.1038/s41467-024-51634-w.

Authors

Chang Liu^#^{1

2

3}, Xiaoyang Dou^#^{1

2}, Yutao Zhao^#^{1

2}, Linda Zhang^{1

2}, Lisheng Zhang^{1

2

4

5}, Qing Dai^{1

2}, Jun Liu^{6

7}, Tong Wu^{1

2}, Yu Xiao^{1

2}, Chuan He^{8

9}

Affiliations

¹ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, 60637, USA.
² Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, 60637, USA.
³ Department of Genetics, School of Medicine, Stanford University, Stanford, CA, 94305, USA.
⁴ Division of Life Science, The Hong Kong University of Science and Technology, Hong Kong, China.
⁵ Department of Chemistry, The Hong Kong University of Science and Technology, Hong Kong, China.
⁶ State Key Laboratory of Protein and Plant Gene Research, School of Life Sciences, Peking-Tsinghua Center for Life Sciences, Peking University, Beijing, 100871, China.
⁷ Beijing Advanced Center of RNA Biology (BEACON), Peking University, Beijing, 100871, China.
⁸ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, Chicago, IL, 60637, USA. chuanhe@uchicago.edu.
⁹ Howard Hughes Medical Institute, The University of Chicago, Chicago, IL, 60637, USA. chuanhe@uchicago.edu.

^# Contributed equally.

Abstract

Recent studies have suggested that mRNA internal m⁷G and its writer protein METTL1 are closely related to cell metabolism and cancer regulation. Here, we identify that IGF2BP family proteins IGF2BP1-3 can preferentially bind internal mRNA m⁷G. Such interactions, especially IGF2BP3 with m⁷G, could promote the degradation of m⁷G target transcripts in cancer cells. IGF2BP3 is more responsive to changes of m⁷G modification, while IGF2BP1 prefers m⁶A to stabilize the bound transcripts. We also demonstrate that p53 transcript, TP53, is m⁷G-modified at its 3'UTR in cancer cells. In glioblastoma, the methylation level and the half lifetime of the modified transcript could be modulated by tuning IGF2BP3, or by site-specific targeting of m⁷G through a dCas13b-guided system, resulting in modulation of cancer progression and chemosensitivity.

MeSH terms

3' Untranslated Regions* / genetics
Adenosine / analogs & derivatives
Adenosine / metabolism
Cell Line, Tumor
Gene Expression Regulation, Neoplastic
Glioblastoma* / genetics
Glioblastoma* / metabolism
Glioblastoma* / pathology
HEK293 Cells
Humans
Methylation
Methyltransferases / genetics
Methyltransferases / metabolism
Mice, Nude
RNA Stability*
RNA, Messenger* / genetics
RNA, Messenger* / metabolism
RNA-Binding Proteins* / genetics
RNA-Binding Proteins* / metabolism
Tumor Suppressor Protein p53 / genetics
Tumor Suppressor Protein p53 / metabolism

Substances

3' Untranslated Regions
Adenosine
IGF2BP1 protein, human
IGF2BP3 protein, human
Methyltransferases
N-methyladenosine
RNA, Messenger
RNA-Binding Proteins
TP53 protein, human
Tumor Suppressor Protein p53

Abstract

MeSH terms

Substances

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