Ddx18-KO Mouse

DDX18, also known as DEAD-box RNA helicase 18, is a crucial regulator of RNA metabolism. It is involved in various cellular processes, including cell cycle control, R-loop homeostasis, and tumorigenesis. It has been associated with pathways such as those related to DNA damage repair, immune escape, and cell-cycle progression, highlighting its overall biological importance. Genetic models, like zebrafish, have been used to study its function [3,6].

In zebrafish, loss-of-function of Ddx18 led to a profound loss of myeloid and erythroid cells, along with apoptosis and G1 cell-cycle arrest, suggesting its essential role in cell-cycle progression in hematopoietic cells [6]. In human cells, DDX18 depletion caused aberrant endogenous R-loop accumulation, DNA-replication defects, and increased sensitivity to DNA-damaging agents, indicating its role in preventing R-loop-induced DNA damage and genome instability [1]. In pancreatic cancer, DDX18 drives tumor immune escape by up-regulating STAT1 expression, and its inhibition can disrupt the immunosuppressive tumor microenvironment [2]. In lung adenocarcinoma, DDX18 knockdown suppresses tumor progression by inducing G1 cell-cycle arrest, while overexpression promotes cell-cycle progression, suggesting it functions as an oncogene through the CDK4-mediated cell-cycle pathway [3]. In colorectal cancer, DDX18 expression is positively correlated with genomic instability markers, and its up-regulation enhances sensitivity to DNA-damaging agents [4]. In gastric cancer, DDX18 promotes cancer cell proliferation, migration, and invasion by affecting the maturation of microRNA-21 [5]. In human head and neck squamous cell carcinoma, knockdown of ALKBH1, which regulates DDX18 expression, inhibited cell proliferation, and exogenous overexpression of DDX18 rescued this arrest [7]. In porcine reproductive and respiratory syndrome virus (PRRSV) infection, DDX18 interacts with viral proteins nsp2 and nsp10, and its silencing down-regulated viral replication [8].

In conclusion, DDX18 plays diverse and essential biological functions in processes like cell-cycle regulation, DNA damage repair, and tumor-related mechanisms. Model-based research, such as in zebrafish, has revealed its significance in normal and disease-related biological processes, especially in cancer development and viral replication. Understanding DDX18 provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Lin, Wen-Ling, Chen, Jung-Kuei, Wen, Xuemei, Paull, Tanya T, Liu, Hung-Wen. . DDX18 prevents R-loop-induced DNA damage and genome instability via PARP-1. In Cell reports, 40, 111089. doi:10.1016/j.celrep.2022.111089. https://pubmed.ncbi.nlm.nih.gov/35858569/

2. Dong, Guoying, Wang, Qin, Wen, Mingxin, Wei, Guangwei, Wang, Yunshan. 2023. DDX18 drives tumor immune escape through transcription-activated STAT1 expression in pancreatic cancer. In Oncogene, 42, 3000-3014. doi:10.1038/s41388-023-02817-0. https://pubmed.ncbi.nlm.nih.gov/37620449/

3. Feng, Bingbing, Wang, Xinying, Qiu, Ding, Zhang, Shuishen, Tang, Ce. 2024. DDX18 Facilitates the Tumorigenesis of Lung Adenocarcinoma by Promoting Cell Cycle Progression through the Upregulation of CDK4. In International journal of molecular sciences, 25, . doi:10.3390/ijms25094953. https://pubmed.ncbi.nlm.nih.gov/38732173/

4. Zhao, Wenchao, Luo, Qingqing, Zhan, Han, Deng, Tan, Duan, Huaxin. 2024. DDX18 influences chemotherapy sensitivity in colorectal cancer by regulating genomic stability. In Experimental cell research, 444, 114344. doi:10.1016/j.yexcr.2024.114344. https://pubmed.ncbi.nlm.nih.gov/39577603/

5. Zhang, Yeqian, Yu, Fengrong, Ni, Bo, Kong, Seong-Ho, Zhu, Chunchao. 2021. The RNA-Binding Protein DDX18 Promotes Gastric Cancer by Affecting the Maturation of MicroRNA-21. In Frontiers in oncology, 10, 598238. doi:10.3389/fonc.2020.598238. https://pubmed.ncbi.nlm.nih.gov/33489896/

6. Payne, Elspeth M, Bolli, Niccolò, Rhodes, Jennifer, Cotter, Finbarr E, Look, A Thomas. 2011. Ddx18 is essential for cell-cycle progression in zebrafish hematopoietic cells and is mutated in human AML. In Blood, 118, 903-15. doi:10.1182/blood-2010-11-318022. https://pubmed.ncbi.nlm.nih.gov/21653321/

7. Guo, Chengli, Liu, Zheming, Zhang, Haojian. 2023. DNA 6mA demethylase ALKBH1 regulates DDX18 expression to promote proliferation of human head and neck squamous cell carcinoma. In Cellular oncology (Dordrecht, Netherlands), 46, 1097-1111. doi:10.1007/s13402-023-00800-1. https://pubmed.ncbi.nlm.nih.gov/36976498/

8. Jin, Huan, Zhou, Lei, Ge, Xinna, Yang, Hanchun, Guo, Xin. 2017. Cellular DEAD-box RNA helicase 18 (DDX18) Promotes the PRRSV Replication via Interaction with Virus nsp2 and nsp10. In Virus research, 238, 204-212. doi:10.1016/j.virusres.2017.05.028. https://pubmed.ncbi.nlm.nih.gov/28648849/