Ddx21, a member of the DEAD-box RNA helicase family, is crucial for various aspects of RNA metabolism, including ribosomal RNA (rRNA) processing, transcription, and translation [5]. It is involved in multiple biological processes such as tissue differentiation, mRNA splicing, and regulation of transcription termination and genome stability [1,2]. In the context of diseases, its elevated expression is observed in most cancers, influencing tumorigenesis, and it also plays a role in host antiviral defense [5].

In epidermal differentiation, glucose binds to the ATP-binding domain of Ddx21, altering its conformation, inhibiting helicase activity, and dissociating its dimers. This leads to Ddx21 re-localization and promotes the splicing of pro-differentiation genes [1]. Ddx21 also mediates co-transcriptional RNA m6A modification by interacting with METTL3 and recognizing R-loops, which is essential for transcription termination and genome stability [2]. In ribosome biogenesis, it coordinates transcription of Pol I-and Pol II-transcribed genes, and in colorectal cancer, its phase separation promotes metastasis via the MCM5-dependent EMT pathway [3,4].

In summary, Ddx21 is essential for RNA metabolism, tissue differentiation, and maintaining genome stability. Its dysregulation is associated with cancer progression, highlighting its potential as a biomarker and therapeutic target. Functional studies, especially those using gene knockout models, have been instrumental in uncovering its roles in these biological processes and disease conditions.

References:

1. Miao, Weili, Porter, Douglas F, Lopez-Pajares, Vanessa, Nolan, Garry P, Khavari, Paul A. . Glucose dissociates DDX21 dimers to regulate mRNA splicing and tissue differentiation. In Cell, 186, 80-97.e26. doi:10.1016/j.cell.2022.12.004. https://pubmed.ncbi.nlm.nih.gov/36608661/

2. Hao, Jin-Dong, Liu, Qian-Lan, Liu, Meng-Xia, Yang, Yun-Gui, Ren, Jie. 2024. DDX21 mediates co-transcriptional RNA m6A modification to promote transcription termination and genome stability. In Molecular cell, 84, 1711-1726.e11. doi:10.1016/j.molcel.2024.03.006. https://pubmed.ncbi.nlm.nih.gov/38569554/

3. Gao, Huabin, Wei, Huiting, Yang, Yang, Wang, Jia, Han, Anjia. 2023. Phase separation of DDX21 promotes colorectal cancer metastasis via MCM5-dependent EMT pathway. In Oncogene, 42, 1704-1715. doi:10.1038/s41388-023-02687-6. https://pubmed.ncbi.nlm.nih.gov/37029300/

4. Calo, Eliezer, Flynn, Ryan A, Martin, Lance, Chang, Howard Y, Wysocka, Joanna. 2014. RNA helicase DDX21 coordinates transcription and ribosomal RNA processing. In Nature, 518, 249-53. doi:10.1038/nature13923. https://pubmed.ncbi.nlm.nih.gov/25470060/

5. Xiao, Yalan, Fan, Jiankun, Li, Zhigang, Hou, Yu. 2024. DDX21 at the Nexus of RNA Metabolism, Cancer Oncogenesis, and Host-Virus Crosstalk: Decoding Its Biomarker Potential and Therapeutic Implications. In International journal of molecular sciences, 25, . doi:10.3390/ijms252413581. https://pubmed.ncbi.nlm.nih.gov/39769343/