Trmt61a is a key component of the RNA N1-methyladenosine-generating methyltransferase complex, often partnering with Trmt6 [1,2,4,5,6,7,8]. This complex is involved in the N1-methyladenosine (m1A) methylation of tRNA, which can impact RNA processing, structure, and the functions of its targets [3]. The m1A modification mediated by Trmt6-Trmt61a complex participates in multiple biological pathways, influencing processes like cell proliferation, differentiation, and stress response, and is thus of great biological importance. Genetic models, such as knockout (KO) or conditional knockout (CKO) mouse models, are valuable for studying its functions.

In aged murine hematopoietic stem cells (HSCs), the Trmt6-Trmt61a complex increases due to declined CRL4DCAF1-mediated ubiquitination degradation signaling. Enforced Trmt6-Trmt61a impairs HSCs through 3'-tiRNA-Leu-CAG and the subsequent RIPK1-RIPK3-MLKL-mediated necroptosis cascade. Deficiency of necroptosis can improve HSC self-renewal capacity [1]. In CD4+ T cells, conditional deletion of the Trmt61a gene in mice causes MYC protein deficiency and cell cycle arrest, disrupting T cell expansion upon antigen stimulation and alleviating colitis in a mouse adoptive transfer colitis model [4]. In hepatocellular carcinoma, Trmt6/Trmt61a-mediated m1A methylation in tRNA is required for liver tumourigenesis, as it elevates m1A methylation in a subset of tRNA to increase PPARδ translation, triggering cholesterol synthesis to activate Hedgehog signaling [2]. In bladder cancer cell lines, depletion of Trmt6/Trmt61a reduces proliferation capacity and cell displacement, and compromises cell survival after induction of cellular stress [6]. In HSCs, Trmt6 deletion promotes HSC proliferation through aberrant activation of mTORC1 signaling, and the Trmt6-Trmt61a complex-mediated tRNA-m1A58 modification regulates HSC homeostasis [8].

In conclusion, Trmt61a, as part of the Trmt6-Trmt61a complex, is crucial for m1A methylation in tRNA, which impacts diverse biological processes. Model-based research, especially KO/CKO mouse models, has revealed its significant roles in diseases such as HSC aging-related decline, liver tumorigenesis, T-cell-mediated colitis, and bladder cancer. Understanding Trmt61a functions provides potential therapeutic targets for these diseases.