Rbm33, an RNA-binding protein, has multiple essential functions. It is involved in regulating mRNA m6A demethylation by forming a complex with ALKBH5, which impacts the tumorigenesis of head-neck squamous cell carcinoma (HNSCC) [1]. It also directs the nuclear export of transcripts containing GC-rich elements, recruiting components of the TREX-NXF1/NXT1 RNA export pathway [2].

In a study on hippocampus aging, hippocampus-specific genetic deletion of Rbm33 alleviated age-related declines in learning and memory in aged Rbm33 knockout (Rbm33-/-) mice, while hippocampus-specific overexpression exacerbated these declines. Mechanistically, Rbm33 forms liquid-liquid phase separation (LLPS) and binds to the CDKN1A (p21cip1) promoter to induce microglial senescence, facilitating hippocampus aging [3].

In conclusion, Rbm33 plays crucial roles in mRNA m6A demethylation-related tumorigenesis, nuclear export of specific transcripts, and hippocampus aging. The use of Rbm33 knockout mouse models has revealed its functions in age-related cognitive decline, highlighting its potential as a therapeutic target for neurodegenerative diseases associated with hippocampal aging [3].

References:

1. Yu, Fang, Zhu, Allen C, Liu, Shun, He, Chuan, Qian, Zhijian. 2023. RBM33 is a unique m6A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity. In Molecular cell, 83, 2003-2019.e6. doi:10.1016/j.molcel.2023.05.010. https://pubmed.ncbi.nlm.nih.gov/37257451/

2. Thomas, Anu, Rehfeld, Frederick, Zhang, He, Gillet, Frank, Mendell, Joshua T. 2022. RBM33 directs the nuclear export of transcripts containing GC-rich elements. In Genes & development, 36, 550-565. doi:10.1101/gad.349456.122. https://pubmed.ncbi.nlm.nih.gov/35589130/

3. Yang, Xiaowen, Wei, Lin, Zhong, Saifeng, Zhang, Yonggang, Yu, Aiqing. 2025. Liquid-liquid phase separation of RBM33 facilitates hippocampus aging by inducing microglial senescence by activating CDKN1A. In International journal of biological macromolecules, 310, 142986. doi:10.1016/j.ijbiomac.2025.142986. https://pubmed.ncbi.nlm.nih.gov/40216137/