Ubiquitin-related modifier 1 (URM1)

Ubiquitin-related modifier 1 (URM1) is a highly conserved ubiquitin-like protein present from yeast to humans, characterized structurally by a β-grasp fold[1][8]. Functionally, URM1 has a dual role: (1) as a protein modifier, it forms covalent conjugates with other proteins in a process termed urmylation—an atypical post-translational modification that is often triggered by oxidative stress and facilitated by its activating enzyme, Uba4 (or MOCS3 in humans)[1][2][4][5][7]. Unlike traditional ubiquitin or other ubiquitin-like pathways, URM1 conjugation is independent of E2/E3 enzymes and is linked to direct redox regulation and cysteine persulfidation[4][5]. (2) As a sulfur carrier protein for tRNA thiolation, URM1 delivers sulfur to specific tRNAs, which is essential for modifying the wobble uridine of tRNA anticodons via the Ncs2-Ncs6 sulfur–transferase complex, optimizing translational efficiency and cellular stress responses[5][6][7]. Loss of URM1-dependent tRNA modifications is associated with broad cellular dysfunction, with links to cancer and neurodegenerative diseases through defective protein translation and stress adaptation[5]. No direct small molecule drugs, clinical biomarkers, or safety concerns are currently identified for URM1, and it is not considered a classical therapeutic target such as an enzyme, receptor, or transporter[1][5][6][7]. URM1 is mainly of interest in fundamental cell biology and evolutionary studies of ubiquitin-like protein modification systems. Key facts: - URM1 is both a post-translational modifier (urmylation substrate conjugator) and a sulfur transfer protein for tRNA modification[1][2][3][5][6][7]. - URM1-mediated sulfur transfer and urmylation are integral to translation and oxidative stress adaptation, but not directly targeted by drugs or established as direct therapeutic targets at present[1][5][6][7]. - Disease links arise from loss of its tRNA modification function—not from targeting the protein directly.

Other names

Ubiquitin-related modifier 1 homologC9orf74MGC2668URM1