NAE1/UBA3-UBE2M are E1 and E2 enzymes for the URM1 modification PMID: 42056084

ADC Targets in Oncology

2026-04-10

NAE1/UBA3-UBE2M are E1 and E2 enzymes for the URM1 modification

Nat Commun. 2026 Apr 29. doi: 10.1038/s41467-026-72296-w.

Swatadipta Chakraborty ¹ , Saibal Chanda ¹ , Zhongwen Cao ² , Alan Pham ³ ⁴ , Zihan Zhang ⁵ ⁶ , Yinsheng Wang ² ⁷ , Logan Herring ⁵ ⁶ , Wenyue Cao ⁸ ⁹ , Wenshe Ray Liu ¹⁰ ¹¹ ¹² ¹³ ¹⁴ ¹⁵ ¹⁶

Affiliations

1. Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA.
2. Environmental Toxicology Graduate Program, University of California, Riverside, CA, USA.
3. Texas A&M Drug Discovery Center, Texas A&M University, College Station, TX, USA.
4. Department of Chemistry, College of Arts and Sciences, Texas A&M University, College Station, TX, USA.
5. Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA.
6. Department of Translational Medical Sciences, Naresh K. Vashisht College of Medicine, Texas A&M University, Houston, TX, USA.
7. Department of Chemistry, University of California, Riverside, CA, USA.
8. Texas A&M Drug Discovery Center, Texas A&M University, College Station, TX, USA. [email protected].
9. Department of Chemistry, College of Arts and Sciences, Texas A&M University, College Station, TX, USA. [email protected].
10. Department of Biochemistry and Biophysics, College of Agriculture and Life Sciences, Texas A&M University, College Station, TX, USA. [email protected].
11. Texas A&M Drug Discovery Center, Texas A&M University, College Station, TX, USA. [email protected].
12. Department of Chemistry, College of Arts and Sciences, Texas A&M University, College Station, TX, USA. [email protected].
13. Institute of Biosciences and Technology, Texas A&M University, Houston, TX, USA. [email protected].
14. Department of Translational Medical Sciences, Naresh K. Vashisht College of Medicine, Texas A&M University, Houston, TX, USA. [email protected].
15. Department of Cell Biology and Genetics, Naresh K. Vashisht College of Medicine, Texas A&M University, College Station, TX, USA. [email protected].
16. Department of Pharmaceutical Sciences, Irma Lerma Rangel College of Pharmacy, Texas A&M University, College Station, TX, USA. [email protected].

Abstract

Ubiquitin-related modifier 1 (URM1) is an evolutionarily conserved ubiquitin-like protein. In eukaryotes, it serves dual roles as a sulfur donor for tRNA modification and a posttranslational protein modifier. URM1 is proposed to be a primitive protein modifier and a potential precursor to the more complex ubiquitin system. However, no specific activating enzyme (E1), conjugating enzyme (E2), or Ligase (E3) has been reported for the URM1 modification cascade in human cells. In this study, we design an activity-based URM1 probe to covalently capture cysteine Enzymes functioning in the URM1 signaling pathway. Through proteomic characterization and cell-based validation, we identify NAE1/UBA3 and UBE2M as E1 and E2 Enzymes, respectively, for the urmylation pathway under both normal and oxidative stress conditions. Pharmacologic perturbation of the UBE2M-DCN1 module suggests DCN1 may contribute to URM1 conjugation. Bioinformatic analysis further reveals that genetic knockdown of NAE1, UBE2M, and URM1 affects overlapping genes associated with pathways controlling cellular response to stress conditions or with implications in liver diseases. URM1 serves a protective role against oxidative stress. Pevonedistat, a potent NAE1 inhibitor that blocks protein urmylation in human cells, exhibits strong synergy with cisplatin, an agent known to induce oxidative stress, in killing liver Cancer cells effectively.