Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs
Summary: 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...
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| Language: | English |
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Elsevier
2025-01-01
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| Series: | Cell Reports |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2211124724014438 |
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| author | Kejia Zhang Aidan C. Manning Jenna M. Lentini Jonathan Howard Felix Dalwigk Reza Maroofian Stephanie Efthymiou Patricia Chan Sergei I. Eliseev Zi Yang Hayley Chang Ehsan Ghayoor Karimiani Behnoosh Bakhshoodeh Henry Houlden Stefanie M. Kaiser Todd M. Lowe Dragony Fu |
| author_facet | Kejia Zhang Aidan C. Manning Jenna M. Lentini Jonathan Howard Felix Dalwigk Reza Maroofian Stephanie Efthymiou Patricia Chan Sergei I. Eliseev Zi Yang Hayley Chang Ehsan Ghayoor Karimiani Behnoosh Bakhshoodeh Henry Houlden Stefanie M. Kaiser Todd M. Lowe Dragony Fu |
| author_sort | Kejia Zhang |
| collection | DOAJ |
| description | Summary: 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. |
| format | Article |
| id | doaj-art-40298f73bdea4d828adeca5b5f72d225 |
| institution | Kabale University |
| issn | 2211-1247 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Cell Reports |
| spelling | doaj-art-40298f73bdea4d828adeca5b5f72d2252025-01-09T06:13:48ZengElsevierCell Reports2211-12472025-01-01441115092Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAsKejia Zhang0Aidan C. Manning1Jenna M. Lentini2Jonathan Howard3Felix Dalwigk4Reza Maroofian5Stephanie Efthymiou6Patricia Chan7Sergei I. Eliseev8Zi Yang9Hayley Chang10Ehsan Ghayoor Karimiani11Behnoosh Bakhshoodeh12Henry Houlden13Stefanie M. Kaiser14Todd M. Lowe15Dragony Fu16Department of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USADepartment of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USADepartment of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USADepartment of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USAInstitute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, GermanyDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, WC1N 3BG London, UKDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, WC1N 3BG London, UKDepartment of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USADepartment of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USADepartment of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USADepartment of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USADepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, WC1N 3BG London, UKMashhad University of Medical Sciences, Mashhad, Razavi Khorasan Province 91778 99191, IranDepartment of Neuromuscular Disorders, UCL Queen Square Institute of Neurology, WC1N 3BG London, UKInstitute of Pharmaceutical Chemistry, Goethe University Frankfurt, Max-von-Laue-Str. 9, 60438 Frankfurt, GermanyDepartment of Biomolecular Engineering, University of California, Santa Cruz, Santa Cruz, CA, USADepartment of Biology, Center for RNA Biology, University of Rochester, Rochester, NY, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2211124724014438CP: Molecular biology |
| spellingShingle | Kejia Zhang Aidan C. Manning Jenna M. Lentini Jonathan Howard Felix Dalwigk Reza Maroofian Stephanie Efthymiou Patricia Chan Sergei I. Eliseev Zi Yang Hayley Chang Ehsan Ghayoor Karimiani Behnoosh Bakhshoodeh Henry Houlden Stefanie M. Kaiser Todd M. Lowe Dragony Fu Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs Cell Reports CP: Molecular biology |
| title | Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs |
| title_full | Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs |
| title_fullStr | Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs |
| title_full_unstemmed | Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs |
| title_short | Human TRMT1 and TRMT1L paralogs ensure the proper modification state, stability, and function of tRNAs |
| title_sort | human trmt1 and trmt1l paralogs ensure the proper modification state stability and function of trnas |
| topic | CP: Molecular biology |
| url | http://www.sciencedirect.com/science/article/pii/S2211124724014438 |
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