Ddx21, a member of the DEAD-box RNA helicase family, is pivotal in multiple RNA metabolic processes such as ribosomal RNA (rRNA) processing, transcription, and translation. It is involved in pathways like mRNA splicing, co-transcriptional RNA m6A modification, and ribosome biogenesis, and is of great biological importance in tissue differentiation, cancer progression, and host-virus crosstalk [1,2,3,4,5,7]. Genetic models are valuable for studying its functions.

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 promotion of pro-differentiation gene splicing [1]. Ddx21 also mediates co-transcriptional RNA m6A modification by interacting with METTL3, promoting transcription termination and genome stability. Loss of Ddx21 leads to defective termination and DNA damage [2]. In ribosome biogenesis, Ddx21 senses the transcriptional status of RNA polymerases I and II, and its disruption impairs rRNA transcription and production [3,5]. In colorectal cancer, high Ddx21 expression promotes metastasis via phase separation and the MCM5-dependent EMT pathway [4]. In acute myeloid leukaemia, knockdown of Ddx21 inhibits cell proliferation, promotes apoptosis, and causes cell cycle arrest [6].

In conclusion, Ddx21 is essential for RNA metabolism, playing key roles in tissue differentiation, cancer progression, and maintaining genome stability. Model-based research, such as gene knockout studies in relevant contexts, has revealed its functions in these biological processes and disease areas, contributing to our understanding of the underlying mechanisms and potentially paving the way for novel therapeutic strategies.

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. Xing, Yu-Hang, Yao, Run-Wen, Zhang, Yang, Yang, Li, Chen, Ling-Ling. . SLERT Regulates DDX21 Rings Associated with Pol I Transcription. In Cell, 169, 664-678.e16. doi:10.1016/j.cell.2017.04.011. https://pubmed.ncbi.nlm.nih.gov/28475895/

4. 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/

5. 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/

6. Zhao, Yanchun, Zhou, Yutong, Qian, Yu, Sun, Jie, Jin, Jie. . m6A-dependent upregulation of DDX21 by super-enhancer-driven IGF2BP2 and IGF2BP3 facilitates progression of acute myeloid leukaemia. In Clinical and translational medicine, 14, e1628. doi:10.1002/ctm2.1628. https://pubmed.ncbi.nlm.nih.gov/38572589/

7. 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/