Trdmt1, also known as DNMT2, is a 5-methylcytosine methyltransferase initially classified 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 widely involved in physiological regulatory processes like gene expression, immune response, and is associated with various diseases including cancer [1,2].

Knockout (KO) of Trdmt1 has been studied in multiple cell models relevant to diseases. In cancer cells, Trdmt1 KO can sensitize them to radiotherapy and chemotherapy [1]. In doxorubicin-treated cancer cell lines (breast, cervical, osteosarcoma, glioblastoma), Trdmt1 KO impaired PERK activation, modulated NSUN and 5-methylcytosine RNA-based responses and microRNA profiles, leading to increased sensitivity to apoptotic cell death during endoplasmic reticulum (ER) stress [3]. In glioblastoma cells, Trdmt1 KO led to decreased levels of total 5-methylcytosine in DNA, DNMT1, and DNMT activity, affecting processes like telomere maintenance, cell cycle, etc. [5]. In a LPS-induced sepsis model in rats, Trdmt1 knockout rats were more vulnerable to LPS treatment, showing that Trdmt1 plays a protective role in inflammation through the TLR4-NF-κB/MAPK-TNF-α pathway [4]. In premature ovarian failure, TRDMT1 mutants with reduced/increased RNA m5C methylation activity severely impaired/enhanced DNA repair in granulosa cells [6].

In summary, Trdmt1 plays essential roles in maintaining normal physiological functions, especially in processes related to DNA and RNA regulation, protein synthesis, and stress response. Studies using Trdmt1 KO models have significantly contributed to understanding its role in cancer, inflammation, and premature ovarian failure, providing potential new therapeutic targets for these diseases.