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.
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.
Mol Cell. 2023 Jun 15;83(12):2003-2019.e6. doi: 10.1016/j.molcel.2023.05.010. Epub 2023 May 30.
Regulation of RNA substrate selectivity of mA demethylase ALKBH5 remains elusive. Here, we identify RNA-binding motif protein 33 (RBM33) as a previously unrecognized mA-binding protein that plays a critical role in ALKBH5-mediated mRNA mA demethylation of a subset of mRNA transcripts by forming a complex with ALKBH5. RBM33 recruits ALKBH5 to its mA-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 mA 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.
RNA 底物选择性的调节仍然难以捉摸。在这里，我们确定 RNA 结合基序蛋白 33（RBM33）为一种先前未被识别的 mA 结合蛋白，它通过与 ALKBH5 形成复合物，在 ALKBH5 介导的一组 mRNA 转录物的 mRNA mA 去甲基化中发挥关键作用。RBM33 将 ALKBH5 招募到其 mA 标记的底物上，并通过去除 SUMOylation 激活 ALKBH5 去甲基酶活性。我们进一步证明 RBM33 对于头颈部鳞状细胞癌（HNSCC）的肿瘤发生至关重要。RBM33 通过招募 ALKBH5 来促进自噬，以去甲基化和稳定 DDIT4 mRNA，这负责 RBM33 在 HNSCC 细胞中的致癌功能。总之，我们的研究揭示了在肿瘤发生过程中选择性地对一组转录物的 mA 甲基化进行去甲基化的机制，这可能解释了其他细胞过程中的去甲基化选择性，并且我们表明其在维持 HNSCC 的肿瘤发生中的重要性。
