TRMT6, short for tRNA methyltransferase 6, is an enzyme that catalyzes N1-methyladenosine (m1A), a reversible modification in various RNAs such as tRNA, mRNA, rRNA, and lncRNA [5]. It often forms a complex with TRMT61A, and this m1A modification participates in regulating RNA processing, structure, and functions, thus influencing gene expression and numerous biological processes [3].

In various disease-related studies, depletion of the TRMT6/TRMT61A complex in bladder cancer cell lines reduced proliferation capacity and cell displacement, and compromised cell survival after cellular stress induction, suggesting its oncogenic role in bladder cancer [6]. In hepatocellular carcinoma, TRMT6 was overexpressed, promoting cell proliferation both in vivo and in vitro through the PI3K/AKT/mTOR axis [2]. In Wilms tumor, the rs236110 C > A polymorphism in the TRMT6 gene was associated with an increased risk of the disease, with the A allele significantly associated with decreased expression of MCM8 [5]. In aged murine hematopoietic stem cells (HSCs), the TRMT6-TRMT61A complex was increased due to declined ubiquitination degradation signaling, and enforced expression of TRMT6-TRMT61A impaired HSCs through a 3'-tiRNA-Leu-CAG-mediated necroptosis cascade [1]. Also, Trmt6 deletion in HSCs promoted their proliferation through aberrant activation of mTORC1 signaling, but led to impaired self-renewal ability, indicating its role in HSC homeostasis [4].

In summary, TRMT6, often in complex with TRMT61A, is crucial in multiple biological processes and disease conditions. Its over-expression or gene polymorphisms are associated with cancers like hepatocellular carcinoma, bladder cancer, and Wilms tumor. In HSCs, it plays a role in maintaining homeostasis, and its dysregulation can lead to HSC impairment. Studies using cell lines and animal models have been instrumental in uncovering these functions, providing insights into potential therapeutic targets for related diseases.

References:

1. He, Hanqing, Wang, Yuqian, Zhang, Xiaoting, Yi, Chengqi, Wang, Jianwei. 2024. Age-related noncanonical TRMT6-TRMT61A signaling impairs hematopoietic stem cells. In Nature aging, 4, 213-230. doi:10.1038/s43587-023-00556-1. https://pubmed.ncbi.nlm.nih.gov/38233630/

2. Ye, Yanqing, Liu, Maosheng, Wu, Fengfei, Xie, Fang, Bai, Lan. 2023. TRMT6 promotes hepatocellular carcinoma progression through the PI3K/AKT signaling pathway. In European journal of medical research, 28, 48. doi:10.1186/s40001-022-00951-1. https://pubmed.ncbi.nlm.nih.gov/36707905/

3. Li, Jiexin, Zhang, Haisheng, Wang, Hongsheng. 2022. N1-methyladenosine modification in cancer biology: Current status and future perspectives. In Computational and structural biotechnology journal, 20, 6578-6585. doi:10.1016/j.csbj.2022.11.045. https://pubmed.ncbi.nlm.nih.gov/36467585/

4. Zuo, Hongna, Wu, Aiwei, Wang, Mingwei, Hong, Liquan, Wang, Hu. 2024. tRNA m1A modification regulate HSC maintenance and self-renewal via mTORC1 signaling. In Nature communications, 15, 5706. doi:10.1038/s41467-024-50110-9. https://pubmed.ncbi.nlm.nih.gov/38977676/

5. Chang, Xiaofeng, Zhu, Jinhong, Hua, Rui-Xi, He, Jing, Wang, Huanmin. 2023. TRMT6 gene rs236110 C > A polymorphism increases the risk of Wilms tumor. In Gene, 882, 147646. doi:10.1016/j.gene.2023.147646. https://pubmed.ncbi.nlm.nih.gov/37473973/

6. Monshaugen, Ida, Luna, Luisa, Rhodes, Jayden, Klungland, Arne, Ougland, Rune. 2024. Depletion of the m1A writer TRMT6/TRMT61A reduces proliferation and resistance against cellular stress in bladder cancer. In Frontiers in oncology, 13, 1334112. doi:10.3389/fonc.2023.1334112. https://pubmed.ncbi.nlm.nih.gov/38304034/