Trdmt1, also known as DNMT2, is a 5-methylcytosine methyltransferase initially misclassified as a DNA methyltransferase. It can methylate both tRNA and mRNA, promoting tRNA stability, proper protein synthesis, and orchestrating DNA damage response (DDR) and DNA stability. It is involved in various physiological regulatory processes such as gene expression, immune response, and is associated with multiple diseases including cancer [1,2].

Gene knockout (KO) studies have provided significant insights. In cancer cells, Trdmt1 KO can sensitize them to radiotherapy and chemotherapy [1]. In a study on doxorubicin-induced endoplasmic reticulum (ER) stress, Trdmt1 KO compromised the unfolded protein response and sensitized cancer cells to ER stress-induced apoptosis [3]. In glioblastoma cells, Trdmt1 KO led to decreased levels of total 5-methylcytosine in DNA, DNMT1, and DNMT activity, and affected DNA methylome-related processes [5]. In rats, Trdmt1 KO made them more vulnerable to LPS-induced inflammation, indicating its protective role in inflammation through the TLR4-NF-κB/MAPK-TNF-α pathway [4]. In granulosa cells, Trdmt1 mutants with reduced/increased RNA m5C methylation activity severely impaired/enhanced DNA repair following reactive oxygen species induction, suggesting its role in the DNA damage repair related to premature ovarian failure [6]. In ovarian cancer, the G155V mutation in Trdmt1 led to hyper-ubiquitination, reduced Trdmt1 levels, impaired homologous recombination, and sensitized cells to cisplatin [7].

In conclusion, Trdmt1 plays essential roles in multiple biological processes and diseases. KO models have been crucial in revealing its functions, such as in cancer response to therapy, inflammation regulation, DNA damage repair, and homologous recombination. These findings contribute to understanding the mechanisms underlying various diseases and suggest Trdmt1 as a potential therapeutic target [1,3,5,7,8].

References:

1. Lewinska, Anna, Adamczyk-Grochala, Jagoda, Wnuk, Maciej. 2023. TRDMT1-mediated RNA C-5 methylation as a novel target in anticancer therapy. In Biochimica et biophysica acta. Reviews on cancer, 1878, 188964. doi:10.1016/j.bbcan.2023.188964. https://pubmed.ncbi.nlm.nih.gov/37625528/

2. Li, Huari, Liu, Huiru, Zhu, Daiyun, Zhang, Mengjie, Wan, Ziyu. 2024. Biological function molecular pathways and druggability of DNMT2/TRDMT1. In Pharmacological research, 205, 107222. doi:10.1016/j.phrs.2024.107222. https://pubmed.ncbi.nlm.nih.gov/38782147/

3. Adamczyk-Grochala, Jagoda, Bloniarz, Dominika, Zielinska, Klaudia, Lewinska, Anna, Wnuk, Maciej. 2022. DNMT2/TRDMT1 gene knockout compromises doxorubicin-induced unfolded protein response and sensitizes cancer cells to ER stress-induced apoptosis. In Apoptosis : an international journal on programmed cell death, 28, 166-185. doi:10.1007/s10495-022-01779-0. https://pubmed.ncbi.nlm.nih.gov/36273376/

4. Li, Zhengguang, Qi, Xiaolong, Zhang, Xu, Zhang, Lianfeng, Ma, Yuanwu. . TRDMT1 exhibited protective effects against LPS-induced inflammation in rats through TLR4-NF-κB/MAPK-TNF-α pathway. In Animal models and experimental medicine, 5, 172-182. doi:10.1002/ame2.12221. https://pubmed.ncbi.nlm.nih.gov/35474613/

5. Zabek, Tomasz, Szmatola, Tomasz, Adamczyk-Grochala, Jagoda, Lewinska, Anna, Wnuk, Maciej. 2023. Knockout of TRDMT1 methyltransferase affects DNA methylome in glioblastoma cells. In Journal of neuro-oncology, 163, 61-69. doi:10.1007/s11060-023-04304-8. https://pubmed.ncbi.nlm.nih.gov/37169948/

6. Sha, Chunli, Chen, Lu, Lin, Li, Li, Yuefeng, Zhu, Xiaolan. 2021. TRDMT1 participates in the DNA damage repair of granulosa cells in premature ovarian failure. In Aging, 13, 15193-15213. doi:10.18632/aging.203080. https://pubmed.ncbi.nlm.nih.gov/34100772/

7. Zhu, Xiaolan, Wang, Xiangyu, Yan, Wei, Li, Hong-Yu, Lan, Li. 2021. Ubiquitination-mediated degradation of TRDMT1 regulates homologous recombination and therapeutic response. In NAR cancer, 3, zcab010. doi:10.1093/narcan/zcab010. https://pubmed.ncbi.nlm.nih.gov/33778494/