Yrdc-KO Mouse

YRDC, or yrdC N6 -threonylcarbamoltransferase domain containing protein, is an essential transfer RNA (tRNA) modification enzyme. It catalyzes the formation of N6 -threonylcarbamoyladenosine (t6A) on ANN-decoding tRNA species, which is crucial for accurate protein synthesis and is associated with pathways like translation [1,5,7,9,10]. It also interacts with the KEOPS complex, playing a role in maintaining genome integrity and telomere homeostasis [5]. Genetic models can be used to study its functions in biological processes and diseases.

Knockdown of YRDC in glioblastoma stem cells reduced t6A formation, suppressed global translation and inhibited tumor growth both in vitro and in vivo. Threonine, an essential substrate of YRDC, accumulated in these cells, facilitating t6A formation and shifting the proteome to support mitosis-related genes [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), knockdown of YRDC in cell lines suppressed cell growth and colony formation and induced apoptosis [3]. In hepatocellular carcinoma, YRDC depletion suppressed proliferation, migration and invasion of cells, while overexpression had the opposite effect, and it promoted progression by activating MEK/ERK signaling pathways [4]. Biallelic variants in YRDC in a patient caused a developmental disorder with progeroid features, due to impaired YRDC function, reduced t6A modifications, telomere shortening and DNA repair defects [5]. In NSCLC cells, RNA structure formation in YRDC 3' UTR can suppress ELAVL1 binding, leading to EGFR-TKI sensitivity by impairing YRDC translation [6]. In osteosarcoma, knockdown of circRBMS3, which can regulate YRDC through 'sponging' miR-424-5p, inhibited malignant phenotypes in vivo [8]. Mutations in YRDC also cause an extremely severe form of Galloway-Mowat syndrome [9].

In conclusion, YRDC is crucial for tRNA modification and accurate protein synthesis. Model-based research, especially through loss-of-function experiments, has revealed its significant roles in multiple diseases such as various cancers, developmental disorders, and Galloway-Mowat syndrome. Understanding YRDC can provide insights into disease mechanisms and potential therapeutic targets.