Wdr4, a component of the methyltransferase 1-WD repeat-containing protein 4 (METTL1-WDR4) complex, is crucial for the N7-methylguanosine (m7G) modification of certain tRNAs at position 46 in the variable loop. This modification is essential for the integrity and stability of a large subset of tRNAs, and thus impacts mRNA translation, cell growth, and is involved in numerous biological processes [1,2]. The METTL1-WDR4 complex is also associated with pathways related to cell cycle regulation, apoptosis, and epithelial-mesenchymal transition (EMT) [3].

In multiple cancer types such as hepatocellular carcinoma, lung cancer, head and neck squamous cell carcinoma, and osteosarcoma, Wdr4 overexpression promotes tumor cell proliferation, metastasis, and drug resistance. For example, in hepatocellular carcinoma, it is activated by c-MYC, promotes CCNB1 mRNA stability and translation, and enhances the activation of PI3K/AKT and ubiquitination of P53 [3]. In lung cancer, knockdown of Wdr4 (along with METTL1) impairs m7G tRNA modification, leading to decreased cell proliferation and invasion [4]. In head and neck squamous cell carcinoma, ablation of METTL1 (in the METTL1-WDR4 complex) reduces m7G levels of 16 tRNAs, inhibiting translation of oncogenic transcripts in the PI3K/AKT/mTOR signaling pathway [5]. In osteosarcoma, knockdown of Wdr4 decreases tRNA m7G modification level and impairs tumor progression [6]. Also, in patients with mutations of Wdr4, cerebellar atrophy and gait phenotypes occur. In a mouse model, Wdr4 deficiency in granule neuron progenitors leads to locomotion defects due to reduced cerebellar foliation and abnormal cell layer organization. Mechanistically, Wdr4 promotes the proliferation of these progenitors by degrading Arhgap17, activating Rac1, and facilitating cell cycle progression [7].

In conclusion, Wdr4 is essential for m7G tRNA modification, which has far-reaching impacts on mRNA translation and cell-related functions. Its dysregulation is closely associated with cancer progression and certain developmental disorders. Studies using gene knockout (KO) or conditional knockout (CKO) mouse models, along with other loss-of-function experiments, have significantly contributed to understanding its role in these disease conditions, providing potential therapeutic targets for related diseases.

References:

1. Li, Jiazhi, Wang, Longfei, Hahn, Quentin, Fischer, Eric S, Gregory, Richard I. 2023. Structural basis of regulated m7G tRNA modification by METTL1-WDR4. In Nature, 613, 391-397. doi:10.1038/s41586-022-05566-4. https://pubmed.ncbi.nlm.nih.gov/36599985/

2. Ruiz-Arroyo, Victor M, Raj, Rishi, Babu, Kesavan, Roberts, Paul H, Nam, Yunsun. 2023. Structures and mechanisms of tRNA methylation by METTL1-WDR4. In Nature, 613, 383-390. doi:10.1038/s41586-022-05565-5. https://pubmed.ncbi.nlm.nih.gov/36599982/

3. Xia, Peng, Zhang, Hao, Xu, Kequan, Zhang, Zhonglin, Yuan, Yufeng. 2021. MYC-targeted WDR4 promotes proliferation, metastasis, and sorafenib resistance by inducing CCNB1 translation in hepatocellular carcinoma. In Cell death & disease, 12, 691. doi:10.1038/s41419-021-03973-5. https://pubmed.ncbi.nlm.nih.gov/34244479/

4. Ma, Jieyi, Han, Hui, Huang, Ying, Li, Wen, Lin, Shuibin. 2021. METTL1/WDR4-mediated m7G tRNA modifications and m7G codon usage promote mRNA translation and lung cancer progression. In Molecular therapy : the journal of the American Society of Gene Therapy, 29, 3422-3435. doi:10.1016/j.ymthe.2021.08.005. https://pubmed.ncbi.nlm.nih.gov/34371184/

5. Chen, Jie, Li, Kang, Chen, Jianwen, Wang, Anxun, Chen, Demeng. 2022. Aberrant translation regulated by METTL1/WDR4-mediated tRNA N7-methylguanosine modification drives head and neck squamous cell carcinoma progression. In Cancer communications (London, England), 42, 223-244. doi:10.1002/cac2.12273. https://pubmed.ncbi.nlm.nih.gov/35179319/

6. Wang, Zhaoyu, Yu, Peng, Zou, Yutong, Liu, Lianlian, Lin, Shuibin. 2023. METTL1/WDR4-mediated tRNA m7G modification and mRNA translation control promote oncogenesis and doxorubicin resistance. In Oncogene, 42, 1900-1912. doi:10.1038/s41388-023-02695-6. https://pubmed.ncbi.nlm.nih.gov/37185458/

7. Wu, Pei-Rung, Chiang, Shang-Yin, Midence, Robert, Huang, Chih-Yang, Chen, Ruey-Hwa. 2023. Wdr4 promotes cerebellar development and locomotion through Arhgap17-mediated Rac1 activation. In Cell death & disease, 14, 52. doi:10.1038/s41419-022-05442-z. https://pubmed.ncbi.nlm.nih.gov/36681682/