Urm1: A Non-Canonical UBL

Biomolecules. 2021 Jan 22;11(2):139. doi: 10.3390/biom11020139.


Urm1 (ubiquitin related modifier 1) is a molecular fossil in the class of ubiquitin-like proteins (UBLs). It encompasses characteristics of classical UBLs, such as ubiquitin or SUMO (small ubiquitin-related modifier), but also of bacterial sulfur-carrier proteins (SCP). Since its main function is to modify tRNA, Urm1 acts in a non-canonical manner. Uba4, the activating enzyme of Urm1, contains two domains: a classical E1-like domain (AD), which activates Urm1, and a rhodanese homology domain (RHD). This sulfurtransferase domain catalyzes the formation of a C-terminal thiocarboxylate on Urm1. Thiocarboxylated Urm1 is the sulfur donor for 5-methoxycarbonylmethyl-2-thiouridine (mcm5s2U), a chemical nucleotide modification at the wobble position in tRNA. This thio-modification is conserved in all domains of life and optimizes translation. The absence of Urm1 increases stress sensitivity in yeast triggered by defects in protein homeostasis, a hallmark of neurological defects in higher organisms. In contrast, elevated levels of tRNA modifying enzymes promote the appearance of certain types of cancer and the formation of metastasis. Here, we summarize recent findings on the unique features that place Urm1 at the intersection of UBL and SCP and make Urm1 an excellent model for studying the evolution of protein conjugation and sulfur-carrier systems.

Keywords: 2-thiolation; non-canonical UBL; rhodanese; sulfur-carrier protein; tRNA modification; thiocarboxylate; ubiquitin-like protein.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Gene Expression Regulation, Fungal
  • Genes, Fungal
  • Homeostasis
  • Phenotype
  • RNA, Transfer / metabolism
  • Saccharomyces cerevisiae / metabolism*
  • Saccharomyces cerevisiae Proteins / metabolism*
  • Small Ubiquitin-Related Modifier Proteins / chemistry*
  • Stress, Physiological
  • Sulfurtransferases / genetics
  • Thiosulfate Sulfurtransferase / chemistry
  • Ubiquitin / chemistry
  • Ubiquitin / metabolism
  • Ubiquitins / metabolism


  • Saccharomyces cerevisiae Proteins
  • Small Ubiquitin-Related Modifier Proteins
  • URM1 protein, S cerevisiae
  • Ubiquitin
  • Ubiquitins
  • RNA, Transfer
  • Sulfurtransferases
  • Thiosulfate Sulfurtransferase