| 2016 |
Crystal structure of human RNMT in complex with the activation domain of RAM revealed that RAM binds a positively charged surface groove on RNMT distal to the active site. Structure-guided mutagenesis and molecular dynamics simulations showed that RAM stabilizes the RNMT lobe structure and the adjacent α-helix hinge, resulting in optimal positioning of helix A which contacts substrates in the active site. RAM allosterically activates RNMT by increasing recruitment of the methyl donor AdoMet (S-adenosyl methionine). |
X-ray crystallography, structure-guided mutagenesis, molecular dynamics simulations, biophysical and biochemical assays |
Nucleic acids research |
High |
27422871
|
| 2016 |
CDK1-cyclin B1 phosphorylates RNMT on T77 within its regulatory domain during G2/M phase of the cell cycle. T77 phosphorylation activates RNMT both directly and by inhibiting its interaction with the RNMT inhibitor KPNA2. This results in elevated m7G cap methyltransferase activity at the beginning of G1 phase, coordinating mRNA capping with the burst of transcription following nuclear envelope reformation. |
Cell cycle synchronization, in vitro kinase assay, phospho-specific antibodies, Co-IP, proliferation assays, phospho-mutant analysis |
Molecular cell |
High |
26942677
|
| 2019 |
Accelerated molecular dynamics simulations provided a detailed allosteric mechanism: RAM selects RNMT active site conformations optimal for substrate (AdoMet and cap) binding, enhancing their affinity. Cap binding likely promotes subsequent AdoMet binding in a cooperative model. Long-range allosteric networks and paths from RAM binding site to the active site were identified. |
Microsecond standard and accelerated molecular dynamics simulations, network community analyses |
Nucleic acids research |
Medium |
31329932
|
| 2018 |
RNMT-RAM promotes RNA Pol II transcription independent of mRNA capping and translation. In isolated nuclei, recombinant RNMT-RAM stimulates transcriptional output in a manner requiring the RAM RNA binding domain. RNMT-RAM interacts with nascent transcripts along their entire length and with transcription-associated factors including RNA Pol II subunits SPT4, SPT6, and PAFc. Suppression of RNMT-RAM inhibits transcriptional markers including histone H2BK120 ubiquitination, H3K4 and H3K36 methylation, RNA Pol II CTD S5 and S2 phosphorylation, and PAFc recruitment. |
RNA Pol II ChIP, nuclear run-on transcription assay, Co-IP/MS interaction studies, siRNA knockdown with transcriptomic readouts, recombinant protein in isolated nuclei |
Cell reports |
High |
29719263
|
| 2013 |
The RNMT N-terminal non-catalytic domain is necessary and sufficient for RNMT recruitment to transcription initiation sites; this recruitment occurs in a DRB-dependent manner. The activating subunit RAM is also recruited to transcription initiation sites via its interaction with RNMT. The N-terminal domain is required for transcript expression, translation, and cell proliferation. |
Fluorescence microscopy with domain deletion/truncation mutants, DRB (transcription inhibitor) treatment, cell proliferation assays |
The Biochemical journal |
Medium |
23863084
|
| 2021 |
RNMT is induced by T cell receptor (TCR) stimulation and coordinates the mRNA, snoRNA, and rRNA production required for ribosome biogenesis. RNMT selectively regulates expression of terminal polypyrimidine tract (TOP) mRNAs, targets of the m7G-cap binding protein LARP1. Conditional knockout of Rnmt in CD4 T cells compromises LARP1 target expression and snoRNA levels, resulting in decreased ribosome synthesis, reduced translation rates, and proliferation failure. |
Conditional knockout (Rnmt cKO) in CD4 T cells, transcriptomics, proteomics, ribosome profiling, proliferation assays |
Nucleic acids research |
High |
34125914
|
| 2022 |
eIF4E directly binds to the methyltransferase domain of RNMT in human cells and in vitro. High-resolution NMR and biochemical studies defined the RNMT-eIF4E binding interface. eIF4E competes with RAM for binding to RNMT, and RNMT competes with established eIF4E-binding partners (4E-BPs). m7G cap-eIF4E-RNMT trimeric complexes can form, suggesting a mechanism by which eIF4E captures newly capped RNA via RNMT. |
Co-IP in human cells, in vitro direct binding assay, high-resolution NMR, competition binding assays |
Journal of molecular biology |
High |
35026230
|
| 2019 |
Oncogenic PIK3CA mutations increase cellular dependency on RNMT for proliferation in breast cancer cells. Expression of oncogenic PIK3CA mutants (increasing PI3Kα activity) was sufficient to increase dependency on RNMT, and inhibition of PI3Kα reversed this dependency, indicating that PI3Kα signaling mediates the enhanced requirement for RNMT. |
siRNA knockdown of RNMT in a panel of breast cancer cell lines, oncogenic PIK3CA expression, PI3Kα inhibitor treatment, proliferation and apoptosis assays |
Open biology |
Medium |
30991934
|
| 2025 |
Two small molecule hits bind competitively with the cap substrate in the RNMT active site pocket. Biophysics, biochemistry, and structural biology confirmed binding affinity of ~1 μM to HsRNMT-RAM in the presence of co-product SAH, resulting in uncompetitive inhibition of cap methyltransferase activity. |
Biophysical binding assays, biochemical inhibition assays, structural biology (crystallography implied) |
The Biochemical journal |
Medium |
39869500
|
| 2025 |
RNMT interacts directly with RNA G-quadruplexes (rG4s), predominantly in the 5' UTR of mRNAs encoding proteins involved in growth and proliferation, providing a mechanism for anchoring RNMT adjacent to the guanosine cap substrate. This rG4 interaction is specific to the RNMT monomer rather than the RNMT-RAM complex, indicating that differential regulation of RNMT vs. RAM can lead to cap methylation of specific RNA subsets. |
CLIP-ART (improved RNA-protein detection method), RNMT monomer vs. RNMT-RAM complex comparison |
bioRxivpreprint |
Medium |
bio_10.1101_2025.11.16.688685
|
| 2025 |
CaMKII phosphorylates RNMT Thr317 on the active site in response to neuronal stimulation, inhibiting methyltransferase activity and targeting RNMT for degradation in the cytoplasm. Following nuclear cap methylation, RNMT is retained on specific mRNAs and translocates to the cytoplasm upon stimulation. RNMT mutants protected from CaMKII-dependent degradation increase locally translated cytoplasmic mRNAs and accelerate neuronal morphogenesis. |
In vitro kinase assay (CaMKII on RNMT), phospho-mutant analysis, live-cell imaging of RNMT translocation, neuronal differentiation assays |
bioRxivpreprint |
Medium |
bio_10.1101_2025.10.30.685591
|
| 2025 |
CYFIP1 collaborates with RNMT to induce m7G methylation of AURKAIP1 mRNA, resulting in stabilization and increased translation of AURKAIP1 mRNA. Increased AURKAIP1 (a mitochondrial small ribosomal subunit protein) expression causes dysregulation of mitochondrial translation, leading to increased FDX1 expression and triggering cuproptosis in osteosarcoma cells. |
Co-IP (CYFIP1-RNMT interaction), mRNA m7G methylation assay, knockdown/overexpression with mRNA stability and translation readouts, in vitro and in vivo osteosarcoma models |
Molecular medicine |
Medium |
39984834
|