| 2014 |
DENR and MCT-1 (MCTS1) form a heterodimeric complex that selectively promotes translation re-initiation after upstream ORFs (uORFs) with strong Kozak sequences, without affecting standard cap-dependent translation initiation. mRNAs containing stuORFs constitute a novel co-regulated class enriched for oncogenic kinases. |
Genetic knockdown/knockout in Drosophila and human cells, polysome profiling, reporter assays, ribosome profiling |
Nature |
High |
25043021
|
| 2017 |
Crystal structure of human DENR-MCT-1 bound to the small (40S) ribosomal subunit revealed that the C-terminal domain of DENR occupies a binding site on the ribosome strikingly similar to that of canonical initiation factor eIF1, which controls translation fidelity and scanning, while MCT-1 contacts helix h24 of 18S rRNA. |
X-ray crystallography of human 40S ribosomal subunit in complex with DENR-MCT-1 |
Cell reports |
High |
28723557
|
| 2018 |
Crystal structure of MCTS1 bound to the N-terminal domain of DENR revealed that DENR residues Glu42, Tyr43, and Tyr46 are critical for MCTS1 binding, and MCTS1 residue Phe104 is critical for tRNA binding. Both DENR-MCTS1 dimerization and tRNA binding are required for translation reinitiation activity in human cells. DENR-MCTS1 can bind tRNA independently of the ribosome, suggesting it recruits tRNA to the ribosome analogously to eIF2. |
X-ray crystallography, site-directed mutagenesis, in vivo translation reinitiation reporter assays, biochemical tRNA binding assays |
PLoS biology |
High |
29889857
|
| 2018 |
Crystal structure of the human MCT-1/DENR N-terminal domain heterodimer at 2.0 Å revealed that four conserved DENR cysteines (C34, C37, C44, C53) form a classical tetrahedral zinc ion-binding site essential for maintaining the MCT-1-binding interface; substitution of all four cysteines with alanine abolished heterodimer formation. |
X-ray crystallography, site-directed mutagenesis, biochemical dimerization assay |
Proceedings of the National Academy of Sciences of the United States of America |
High |
30584092
|
| 2018 |
In yeast, Tma22 (DENR ortholog), Tma20 (MCT-1 ortholog), and Tma64 (eIF2D ortholog) function as 40S ribosomal subunit recycling factors in vivo at stop codons; deletion of these genes causes 80S ribosomes to queue at stop codons and enables aberrant reinitiation including at 3' UTR AUG codons. |
Ribosome profiling of yeast tma deletion strains, 3' UTR reporter assays, in vitro translation |
Molecular cell |
High |
30146315
|
| 2020 |
DENR and MCTS1 are required for translational induction of ATF4 upon cellular stress by promoting translation reinitiation in the ATF4 5' UTR. DENR and MCTS1 are specifically needed for reinitiation after uORFs containing certain penultimate codons, suggesting they are required to evict specific tRNAs from post-termination 40S ribosomes. |
DENR/MCTS1 knockdown in human cells, polysome profiling, ATF4 reporter assays, ribosome profiling |
Nature communications |
High |
32938922 32938929
|
| 2020 |
DENR and eIF2D are required for ATF4 translational induction in the integrated stress response in Drosophila and human cells. Loss of eIF2D and DENR in Drosophila causes increased vulnerability to amino acid deprivation and ER stress phenotypes similar to ATF4 mutants. eIF2D requires its RNA-binding motif for regulation of 5' leader-mediated ATF4 translation. |
Drosophila genetics (loss-of-function), human cell knockdown, ATF4 5' UTR reporter assays, RNA-binding domain mutagenesis |
Nature communications |
High |
32938922 32938929
|
| 2020 |
Crystal structure of the C-terminal domain of DENR at 1.74 Å resolution confirmed its structural resemblance to eIF1, consistent with its binding site on the ribosome near the P site and its role in initiation codon selection and scanning. |
X-ray crystallography |
Computational and structural biotechnology journal |
High |
32257053
|
| 2021 |
In yeast, the Tma20/Tma22 (MCT-1/DENR) heterodimer is responsible for the majority of 40S ribosomal subunit recycling events at stop codons, while Tma64 (eIF2D) plays only a minor role. An autism-associated mutation in TMA22 (DENR) causes loss of 40S recycling activity, directly linking ribosome recycling to neurological disease. |
40S ribosome footprinting (selective ribosome profiling), yeast deletion and point-mutant strains |
Nature communications |
High |
34016977
|
| 2016 |
DENR, together with its binding partner MCTS1, is required for cortical neuron migration and dendritic arborization in vivo. De novo missense mutations in DENR (p.C37Y and p.P121L) found in patients with brain developmental disorders impair DENR function in mRNA translation re-initiation and disrupt cortical neuron migration and terminal branching. |
In utero electroporation in mice (loss-of-function), human patient variant characterization, translation re-initiation reporter assays |
Cell reports |
High |
27239039
|
| 2017 |
In human cells, DENR and MCTS1 selectively promote translation of mRNAs with very short stuORFs (coding for 1 amino acid), identifying approximately 100 target genes enriched for neuronal genes and G protein-coupled receptors. |
DENR/MCTS1 knockdown, polysome profiling, ribosome footprinting, reporter assays in human cells |
Scientific reports |
Medium |
28623304
|
| 2019 |
DENR promotes translation reinitiation on the Clock mRNA via a specific uORF in its 5' UTR, thereby regulating CLOCK protein biosynthesis and influencing circadian period length in mouse fibroblasts. DENR depletion shortens circadian period. |
Ribosome profiling in DENR-deficient NIH3T3 cells, Clock 5' UTR mutant reporter assays, circadian period measurement |
Nucleic acids research |
High |
30982898
|
| 2022 |
DENR is phosphorylated on Serine 73 by Cyclin B/CDK1 and Cyclin A/CDK2 at the onset of mitosis and dephosphorylated as cells exit mitosis. Ser73 phosphorylation promotes DENR protein stability by preventing cleavage at Asp26, leading to enhanced translation of mitotically relevant mRNAs (~40% of translationally upregulated mitotic mRNAs are DENR targets). Absence of DENR or Ser73 phosphorylation causes elevated aberrant mitoses and cell death. |
Cell synchronization, phospho-specific antibodies, CDK inhibitor and mutagenesis experiments, ribosome profiling in mitotic cells, live-cell imaging |
Nature communications |
High |
35115540
|
| 2022 |
DENR promotes JAK2 translation by antagonizing translational repression mediated by three consecutive uORFs in the Jak2 5' UTR. DENR deficiency impairs JAK2 protein expression, reduces IFNγ-JAK-STAT signaling, and consequently decreases PD-L1 expression, thereby reducing tumor immune evasion. |
CRISPR/Cas9 screening, DENR knockdown/knockout in cancer cells, JAK2 uORF reporter assays, in vivo tumor models, FACS for PD-L1 and CD8+ T cell activity |
Nature communications |
High |
35440133
|
| 2007 |
AUF1 RNA-binding protein binds to discrete ARE-containing regions in the DENR mRNA 3' UTR in a cell-density-dependent manner, and AUF1 silencing increases DENR protein levels, establishing post-transcriptional regulation of DENR expression. |
RNA immunoprecipitation, Western blotting, AUF1 shRNA knockdown in HEK293 cells |
Cancer genomics & proteomics |
Medium |
17878526
|
| 2025 |
DENR promotes ATF4 expression via uORF-mediated translational reinitiation, and DENR-driven ATF4 signaling inhibits ferroptosis in esophageal squamous cell carcinoma cells, reducing cisplatin sensitivity. Silencing ATF4 partially reverses DENR-mediated ferroptosis inhibition and DDP resistance. |
DENR overexpression and knockdown, ATF4 knockdown epistasis, ROS/Fe2+ measurement, in vivo xenograft tumor assays |
Biochemical and biophysical research communications |
Medium |
41237468
|