Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs
The tRNA methyltransferase 1 (TRMT1) enzyme catalyzes the N2,N2-dimethylguanosine (m2,2G) modification in tRNAs. Intriguingly, vertebrates encode an additional tRNA methyltransferase 1-like (TRMT1L) paralog. Here, we use a comprehensive tRNA sequencing approach to decipher targets of human TRMT1 and TRMT1L. We find that TRMT1 methylates all known tRNAs containing guanosine at position 26, while TRMT1L represents the elusive enzyme catalyzing m2,2G at position 27 in tyrosine tRNAs. Surprisingly, TRMT1L is also necessary for maintaining 3-(3-amino-3-carboxypropyl)uridine (acp3U) modifications in a subset of tRNAs through a process that can be uncoupled from methyltransferase activity. We also demonstrate that tyrosine and serine tRNAs are dependent upon m2,2G modifications for their stability and function in translation. Notably, human patient cells with disease-associated TRMT1 variants exhibit reduced levels of tyrosine and serine tRNAs. These findings uncover unexpected roles for TRMT1 paralogs, decipher functions for m2,2G modifications, and pinpoint tRNAs dysregulated in human disorders caused by tRNA modification deficiency.
Authors
- Jonathan C. Howard (ORCID: https://orcid.org/0000-0003-2756-5143)
- Todd M. Lowe (ORCID: https://orcid.org/0000-0003-3253-6021)
- Stéphanie Efthymiou (ORCID: https://orcid.org/0000-0003-4900-9877)
- Dragony Fu (ORCID: https://orcid.org/0000-0002-8725-8658)
- Jenna M. Lentini (ORCID: https://orcid.org/0000-0002-4069-4102)
- Aidan C. Manning (ORCID: https://orcid.org/0000-0001-9369-6008)
- Ehsan Ghayoor Karimiani (ORCID: https://orcid.org/0000-0003-3858-7073)
- Patricia P. Chan (ORCID: https://orcid.org/0000-0003-0810-1642)
- Henry Houlden (ORCID: https://orcid.org/0000-0002-2866-7777)
- Reza Maroofian (ORCID: https://orcid.org/0000-0001-6763-1542)
- Felix Dalwigk
- Kejia Zhang (ORCID: https://orcid.org/0000-0002-1089-6782)
- Zi Yang (ORCID: https://orcid.org/0009-0003-9161-6299)
- Behnoosh Bakhshoodeh
- Sergei I. Eliseev
- Stefanie Kaiser (ORCID: https://orcid.org/0000-0003-3224-7502)
- Hayley Chang
Institutions
- Goethe University Frankfurt (DE)
- Mashhad University of Medical Sciences (IR)
- University of California, Santa Cruz (US)
- National Hospital for Neurology and Neurosurgery (GB)
- University College London (GB)
- University of Rochester (US)
Publication Details
- Journal
- Cell Reports
- Published
- 2025-01-01
- DOI
- https://doi.org/10.1016/j.celrep.2024.115092
- Citations
- 14
- Primary Topic
- RNA modifications and cancer
- Type
- article
- Field-Weighted Citation Impact
- 11.28
Funders
- National Science Foundation
- Muscular Dystrophy Association
- University of Rochester
- Wellcome Trust
- Muscular Dystrophy UK
- National Institute for Health and Care Research
- Ataxia UK
- University College London
- Rosetrees Trust
- Great Ormond Street Hospital Charity
- Deutsche Forschungsgemeinschaft
- National Institutes of Health
- Medical Research Council