@article{5ba96ed377e1467582a6e1639875ab2a,
title = "RBM33 is a unique m6A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity",
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, head and neck squamous cell sarcinoma, HNSCC, m6A RNA modification, RBM33 RNA-binding protein, substrate selectivity",
author = "Fang Yu and Zhu, {Allen C.} and Shun Liu and Boyang Gao and Yuzhi Wang and Nelli Khudaverdyan and Chunjie Yu and Qiong Wu and Yunhan Jiang and Jikui Song and Lingtao Jin and Chuan He and Zhijian Qian",
note = "Funding Information: We thank all members of Z.Q.{\textquoteright}s laboratory for their valuable discussions. This work was partially supported by National Institutes of Health (NIH) RO1 grants R01 HL157539-01 (Z.Q.), DK129489 (Z.Q.), CA259576-01 (Z.Q.), R01CA266659 (Z.Q.), and RM1 HG008935 (C.H.). Z.Q. is a Leukemia & Lymphoma Society (LLS) Scholar. C.H. is an investigator of the Howard Hughes Medical Institute (HHMI). Funding Information: We thank all members of Z.Q.{\textquoteright}s laboratory for their valuable discussions. This work was partially supported by National Institutes of Health (NIH) RO1 grants R01 HL157539-01 (Z.Q.), DK129489 (Z.Q.), CA259576-01 (Z.Q.), R01CA266659 (Z.Q.), and RM1 HG008935 (C.H.). Z.Q. is a Leukemia & Lymphoma Society (LLS) Scholar. C.H. is an investigator of the Howard Hughes Medical Institute (HHMI). Z.Q. and F.Y. conceived the project. Z.Q and C.H. supervised the experiments. F.Y. A.C.Z. B.G. Y.W. N.K. C.Y. Q.W. and Y.J. conducted experiments and interpreted the data. A.C.Z. performed RNA-seq, m6A-seq, and RIP-seq. A.C.Z. and S.L. analyzed RNA-seq, m6A-seq, and RIP-seq data. J.S. analyzed the electrostatic surfaces of all the AlkB family demethylases and displayed the amino acids in the interaction interface between RBM33 and ALKBH5. Y.J. and L.J. provided reagents, HNSCC cell lines, and advice for the project. F.Y. and Z.Q. wrote the manuscript with input from all the other authors. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Publisher Copyright: {\textcopyright} 2023 Elsevier Inc.",
year = "2023",
month = jun,
day = "15",
doi = "10.1016/j.molcel.2023.05.010",
language = "English (US)",
volume = "83",
pages = "2003--2019.e6",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "12",
}