RBM33 is a unique m6A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity

Fang Yu; Allen C Zhu; Shun Liu; Boyang Gao; Yuzhi Wang; Nelli Khudaverdyan; Chunjie Yu; Qiong Wu; Yunhan Jiang; Jikui Song; Lingtao Jin; Chuan He; Zhijian Qian

doi:10.1016/j.molcel.2023.05.010

RBM33 is a unique m⁶A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity

Mol Cell. 2023 Jun 15;83(12):2003-2019.e6. doi: 10.1016/j.molcel.2023.05.010. Epub 2023 May 30.

Authors

Fang Yu¹, Allen C Zhu², Shun Liu², Boyang Gao², Yuzhi Wang³, Nelli Khudaverdyan⁴, Chunjie Yu⁵, Qiong Wu⁵, Yunhan Jiang⁶, Jikui Song⁴, Lingtao Jin⁶, Chuan He⁷, Zhijian Qian⁸

Affiliations

¹ Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA; Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA.
² Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA.
³ Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA.
⁴ Department of Biochemistry, University of California, Riverside, CA 92521, USA.
⁵ Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA.
⁶ Department of Molecular Medicine, UT Health San Antonio, 7703 Floyd Curl Drive, San Antonio, TX 78229, USA.
⁷ Department of Chemistry, Department of Biochemistry and Molecular Biology, and Institute for Biophysical Dynamics, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA; Howard Hughes Medical Institute, The University of Chicago, 929 East 57th Street, Chicago, IL 60637, USA. Electronic address: chuanhe@uchicago.edu.
⁸ Department of Medicine, UF Health Cancer Center, University of Florida, Gainesville, FL 32610, USA; Department of Medicine and Department of Biochemistry and Molecular Biology, University of Florida, Gainesville, FL 32610, USA. Electronic address: zhijian.qian@medicine.ufl.edu.

PMID: 37257451
PMCID: PMC10330838 (available on 2024-06-15)
DOI: 10.1016/j.molcel.2023.05.010

Abstract

Regulation of RNA substrate selectivity of m⁶A demethylase ALKBH5 remains elusive. Here, we identify RNA-binding motif protein 33 (RBM33) as a previously unrecognized m⁶A-binding protein that plays a critical role in ALKBH5-mediated mRNA m⁶A demethylation of a subset of mRNA transcripts by forming a complex with ALKBH5. RBM33 recruits ALKBH5 to its m⁶A-marked substrate and activates ALKBH5 demethylase activity through the removal of its SUMOylation. We further demonstrate that RBM33 is critical for the tumorigenesis of head-neck squamous cell carcinoma (HNSCC). RBM33 promotes autophagy by recruiting ALKBH5 to demethylate and stabilize DDIT4 mRNA, which is responsible for the oncogenic function of RBM33 in HNSCC cells. Altogether, our study uncovers the mechanism of selectively demethylate m⁶A methylation of a subset of transcripts during tumorigenesis that may explain demethylation selectivity in other cellular processes, and we showed its importance in the maintenance of tumorigenesis of HNSCC.

Keywords: ALKBH5 RNA demethylase; DDIT4; HNSCC; RBM33 RNA-binding protein; head and neck squamous cell sarcinoma; m6A RNA modification; substrate selectivity.

MeSH terms

AlkB Homolog 5, RNA Demethylase* / genetics
AlkB Homolog 5, RNA Demethylase* / metabolism
Carcinogenesis
Head and Neck Neoplasms*
Humans
RNA, Messenger / genetics
RNA, Messenger / metabolism
RNA-Binding Proteins / genetics
Squamous Cell Carcinoma of Head and Neck / genetics

Substances

AlkB Homolog 5, RNA Demethylase
RNA, Messenger
RNA-Binding Proteins
ALKBH5 protein, human

Abstract

MeSH terms

Substances

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