ArticleProtein science : a publication of the Protein Society2017
Select human cancer mutants of NRMT1 alter its catalytic activity and decrease N-terminal trimethylation.
Article in Protein science : a publication of the Protein Society, 2017. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
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Who cites it
21 citing papers in PubMed, 32 citations in OpenAlex.
- Integrative epitranscriptomic and transcriptomic characterization in human colorectal cancer.Journal of advanced research · 2026Article
- The methyltransferase-like proteins as core regulators of nucleic acid modifications and post-translation modification of proteins in disease pathogenesis and therapeutic implications.Biomarker research · 2025Review
- Generation and characterization of two acid-resistant macrocinComputational and structural biotechnology journal · 2024Article
- Opposing regulation of the Nα-trimethylase METTL11A by its family members METTL11B and METTL13.The Journal of biological chemistry · 2023Article
- Three's a crowd - why did three N-terminal methyltransferases evolve for one job?Journal of cell science · 2023Article
- METTLing in Stem Cell and Cancer Biology.Stem cell reviews and reports · 2023Review
- Article
- Design and characterization of PROTAC degraders specific to protein N-terminal methyltransferase 1.European journal of medicinal chemistry · 2022Article
- Genome-Wide Super-Enhancer-Based Analysis: Identification of Prognostic Genes in Oral Squamous Cell Carcinoma.International journal of molecular sciences · 2022Article
- Improved Cell-Potent and Selective Peptidomimetic Inhibitors of Protein N-Terminal Methyltransferase 1.Molecules (Basel, Switzerland) · 2022Article
- Modulation of N-terminal methyltransferase 1 by an NBiochemical and biophysical research communications · 2021Article
- Selective Peptidomimetic Inhibitors of NTMT1/2: Rational Design, Synthesis, Characterization, and Crystallographic Studies.Journal of medicinal chemistry · 2020Article
- Histone N-alpha terminal modifications: genome regulation at the tip of the tail.Epigenetics & chromatin · 2020Review
- Article
- Chemical Biology of Protein N-Terminal Methyltransferases.Chembiochem : a European journal of chemical biology · 2019Review
- N-terminal acetylation and methylation differentially affect the function of MYL9.The Biochemical journal · 2018Article
- The N-terminal methyltransferase homologs NRMT1 and NRMT2 exhibit novel regulation of activity through heterotrimer formation.Protein science : a publication of the Protein Society · 2018Article
- The ribosome: A hot spot for the identification of new types of protein methyltransferases.The Journal of biological chemistry · 2018Article
- An asparagine/glycine switch governs product specificity of human N-terminal methyltransferase NTMT2.Communications biology · 2018Article
- Article
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Authors and funding
8 authors at 3 institutions in 1 country.
Funding
Abstract
A subset of B-cell lymphoma patients have dominant mutations in the histone H3 lysine 27 (H3K27) methyltransferase EZH2, which change it from a monomethylase to a trimethylase. These mutations occur in aromatic resides surrounding the active site and increase growth and alter transcription. We study the N-terminal trimethylase NRMT1 and the N-terminal monomethylase NRMT2. They are 50% identical, but differ in key aromatic residues in their active site. Given how these residues affect EZH2 activity, we tested whether they are responsible for the distinct catalytic activities of NRMT1/2. Additionally, NRMT1 acts as a tumor suppressor in breast cancer cells. Its loss promotes oncogenic phenotypes but sensitizes cells to DNA damage. Mutations of NRMT1 naturally occur in human cancers, and we tested a select group for altered activity. While directed mutation of the aromatic residues had minimal catalytic effect, NRMT1 mutants N209I (endometrial cancer) and P211S (lung cancer) displayed decreased trimethylase and increased monomethylase/dimethylase activity. Both mutations are located in the peptide-binding channel and indicate a second structural region impacting enzyme specificity. The NRMT1 mutants demonstrated a slower rate of trimethylation and a requirement for higher substrate concentration. Expression of the mutants in wild type NRMT backgrounds showed no change in N-terminal methylation levels or growth rates, demonstrating they are not acting as dominant negatives. Expression of the mutants in cells lacking endogenous NRMT1 resulted in minimal accumulation of N-terminal trimethylation, indicating homozygosity could help drive oncogenesis or serve as a marker for sensitivity to DNA damaging chemotherapeutics or γ-irradiation.
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