YRDC, also known as yrdC N6 -threonylcarbamoltransferase domain containing protein, is essential for the formation of N6 -threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species. This modification is crucial for accurate protein synthesis, and YRDC may interact with the KEOPS complex in this process [5,7,9,10]. It is involved in multiple biological pathways such as translation, and its dysregulation has implications for various biological processes and diseases [1-6,8,9]. Genetic models can be valuable for studying its functions.

Knockdown of YRDC in glioblastoma stem cells (GSCs) reduced t6A formation, suppressed global translation, and inhibited tumor growth both in vitro and in vivo. Threonine, an essential substrate of YRDC, accumulated in GSCs, facilitating t6A formation and shifting the proteome to support mitosis-related genes. Dietary threonine restriction also reduced tumor t6A formation and slowed xenograft growth [1]. In hepatocarcinoma cells, YRDC knockdown decreased susceptibility to lenvatinib, and it was found to regulate the protein translation of KRAS [2]. In non-small cell lung cancer (NSCLC), YRDC knockdown suppressed cell growth, colony formation, and induced apoptosis [3]. In hepatocellular carcinoma, YRDC depletion suppressed cell proliferation, migration, and invasion [4]. In a patient with a severe neonatal progeroid phenotype, a YRDC mutation impaired its function, reduced t6A modifications of tRNAs, led to telomere shortening, and caused significant transcriptome-wide changes [5]. In NSCLC cells, RNA structure formation in YRDC 3' UTR affected its translation and modulated resistance to EGFR-TKIs [6]. In osteosarcoma, knockdown of a circular RNA (circRBMS3) that regulates YRDC inhibited malignant phenotypes in vivo [8]. Mutations in YRDC cause an extremely severe form of Galloway-Mowat syndrome [9].

In conclusion, YRDC is crucial for t6A modification on tRNA, which is essential for accurate translation. Model-based research, especially loss-of-function experiments, has revealed its role in multiple disease conditions such as glioblastoma, hepatocarcinoma, NSCLC, and Galloway-Mowat syndrome. Understanding YRDC's functions provides insights into disease mechanisms and potential therapeutic targets.

References:

1. Wu, Xujia, Yuan, Huairui, Wu, Qiulian, Zhang, Nu, Rich, Jeremy N. 2024. Threonine fuels glioblastoma through YRDC-mediated codon-biased translational reprogramming. In Nature cancer, 5, 1024-1044. doi:10.1038/s43018-024-00748-7. https://pubmed.ncbi.nlm.nih.gov/38519786/

2. Guo, Jun, Zhu, Peng, Ye, Zhi, Zhou, Honghao, Li, Qing. 2021. YRDC Mediates the Resistance of Lenvatinib in Hepatocarcinoma Cells via Modulating the Translation of KRAS. In Frontiers in pharmacology, 12, 744578. doi:10.3389/fphar.2021.744578. https://pubmed.ncbi.nlm.nih.gov/34658879/

3. Shen, Haibo, Zheng, Enkuo, Yang, Zhenhua, Li, Rui, Zhao, Guofang. 2020. YRDC is upregulated in non-small cell lung cancer and promotes cell proliferation by decreasing cell apoptosis. In Oncology letters, 20, 43-52. doi:10.3892/ol.2020.11560. https://pubmed.ncbi.nlm.nih.gov/32565932/

4. Huang, Shiqiong, Zhu, Peng, Sun, Bao, Shu, Yan, Li, Qing. 2019. Modulation of YrdC promotes hepatocellular carcinoma progression via MEK/ERK signaling pathway. In Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie, 114, 108859. doi:10.1016/j.biopha.2019.108859. https://pubmed.ncbi.nlm.nih.gov/30978526/

5. Schmidt, Julia, Goergens, Jonas, Pochechueva, Tatiana, Yigit, Gökhan, Wollnik, Bernd. 2021. Biallelic variants in YRDC cause a developmental disorder with progeroid features. In Human genetics, 140, 1679-1693. doi:10.1007/s00439-021-02347-3. https://pubmed.ncbi.nlm.nih.gov/34545459/

6. Shi, Boyang, An, Ke, Wang, Yueqin, Tian, Xin, Kan, Quancheng. 2022. RNA Structural Dynamics Modulate EGFR-TKI Resistance Through Controlling YRDC Translation in NSCLC Cells. In Genomics, proteomics & bioinformatics, 21, 850-865. doi:10.1016/j.gpb.2022.10.006. https://pubmed.ncbi.nlm.nih.gov/36435452/

7. Harris, Kimberly A, Jones, Victoria, Bilbille, Yann, Swairjo, Manal A, Agris, Paul F. 2011. YrdC exhibits properties expected of a subunit for a tRNA threonylcarbamoyl transferase. In RNA (New York, N.Y.), 17, 1678-87. doi:10.1261/rna.2592411. https://pubmed.ncbi.nlm.nih.gov/21775474/

8. Gong, Zhe, Shen, Panyang, Wang, Haitao, Fang, Xiangqian, Liu, Gang. 2023. A novel circular RNA circRBMS3 regulates proliferation and metastasis of osteosarcoma by targeting miR-424-eIF4B/YRDC axis. In Aging, 15, 1564-1590. doi:10.18632/aging.204567. https://pubmed.ncbi.nlm.nih.gov/36897170/

9. Arrondel, Christelle, Missoury, Sophia, Snoek, Rozemarijn, van Tilbeurgh, Herman, Mollet, Géraldine. 2019. Defects in t6A tRNA modification due to GON7 and YRDC mutations lead to Galloway-Mowat syndrome. In Nature communications, 10, 3967. doi:10.1038/s41467-019-11951-x. https://pubmed.ncbi.nlm.nih.gov/31481669/

10. El Yacoubi, Basma, Lyons, Benjamin, Cruz, Yulien, Swairjo, Manal A, de Crécy-Lagard, Valérie. 2009. The universal YrdC/Sua5 family is required for the formation of threonylcarbamoyladenosine in tRNA. In Nucleic acids research, 37, 2894-909. doi:10.1093/nar/gkp152. https://pubmed.ncbi.nlm.nih.gov/19287007/