| 2022 |
SMYD5 is a histone methyltransferase that catalyzes H3K36me3 at promoter regions (distinct from SETD2-mediated H3K36me3 at gene bodies). SMYD5 is recruited to chromatin by RNA polymerase II, and its enzymatic activity depends on its C-terminal glutamic acid-rich domain; overexpression of full-length but not C-terminal domain-truncated Smyd5 restores H3K36me3 at promoters in knockout cells. |
ChIP-seq, Smyd5 knockout rescue with full-length vs. truncated constructs, in vitro methyltransferase assay |
Nature communications |
High |
35680905
|
| 2024 |
SMYD5 trimethylates the core ribosomal protein RPL40 (ubiquitin fusion protein partner) at lysine 22 (rpL40K22me3). This modification regulates mRNA translation output; loss of SMYD5 leads to reduced translation output and increased ribosome collisions indicative of disturbed elongation. Identified by a biochemical-proteomics strategy as the principal physiological substrate of SMYD5. |
Biochemical-proteomics (mass spectrometry), in vitro methyltransferase assay, ribosome profiling/polysome analysis, SMYD5 ablation in cell lines and mouse models |
Nature |
High |
39048817
|
| 2024 |
SMYD5 has robust in vitro methyltransferase activity toward RPL40 K22 and primarily catalyzes RPL40 K22me3 in cells. Loss of SMYD5 and RPL40 K22me3 reduces translation output and causes increased ribosome collisions. SMYD5 and RPL40 K22me3 are upregulated in hepatocellular carcinoma. |
In vitro methyltransferase assay with recombinant SMYD5, SMYD5 knockout cell lines, ribosome fractionation/polysome profiling, genetically engineered mouse models and PDX models |
Cell research |
High |
39103523
|
| 2025 |
SMYD5 trimethylates RPL40/eL40 at lysine 22 through recognition of a KXY motif (tyrosine at the +2 position is required). Active site mutations abolish this activity. SMYD5 does not methylate histones in vitro, and its requirement for the KXY motif explains this lack of activity toward canonical histone substrates. SMYD5 KO in K562 cells causes complete loss of RPL40 K22 methylation and decreased polysome levels. |
In vitro methyltransferase assay with recombinant SMYD5 and synthetic peptides, active-site mutagenesis, SMYD5 KO in K562 cells, mass spectrometry, systematic recognition motif analysis |
Cell reports |
High |
40184250
|
| 2025 |
SMYD5 does not methylate histones in vitro (negative finding). Systematic analysis of its recognition motif shows SMYD5 requires a KXY motif, and the absence of a tyrosine at +2 in canonical histone substrates explains its lack of histone methyltransferase activity. |
In vitro methyltransferase assay with recombinant SMYD5 toward histone substrates, systematic peptide motif analysis |
Cell reports |
High |
40184250
|
| 2017 |
SMYD5 mediates H4K20me3 at heterochromatin regions in embryonic stem cells. Depletion of SMYD5 leads to global decreases in H4K20me3 levels, redistribution of heterochromatin constituents (H3K9me3/2, G9a, HP1α), and de-repression of endogenous retroelements (LTR, LINE elements). Loss of SMYD5-dependent heterochromatin silencing near genic regions upregulates lineage-specific genes, compromising ES cell self-renewal. |
ChIP-seq, SMYD5 knockdown in mouse ES cells, Western blot for histone marks, repeat element expression analysis |
Epigenetics & chromatin |
Medium |
28250819
|
| 2017 |
SMYD5 depletion during ES cell differentiation causes genome-wide decreases in H4K20me3 and H3K9me3, derepression of LTR and LINE repetitive elements, chromosomal aberrations, and formation of transformed cells with a cancer-like expression signature. Depletion of SMYD5 in human colon and lung cancer cells increases tumor growth. |
SMYD5 depletion in mouse ES cells during differentiation, ChIP-seq, cytogenetics/karyotyping, xenograft tumor assays |
Cancer research |
Medium |
28951459
|
| 2022 |
SMYD5 interacts with PGC-1α (co-immunoprecipitation) and mediates lysine methylation of PGC-1α, subsequently facilitating its ubiquitination and degradation. This post-translational mechanism attenuates mitochondrial biogenesis, respiration, and function in intestinal epithelial cells. Smyd5 conditional knockout in IECs protects mice from DSS-induced colitis. |
Co-immunoprecipitation, in vitro methylation assay with mass spectrometry identification of methylated lysines, cycloheximide chase assay, Smyd5 conditional KO mice with colitis model, Seahorse respirometry |
Cellular and molecular gastroenterology and hepatology |
Medium |
35643234
|
| 2023 |
SMYD5 associates in vivo with the HIV-1 promoter, binds the HIV-1 TAR element RNA and Tat protein, and methylates Tat in vitro. SMYD5 activates the HIV-1 promoter with or without Tat; knockdown of SMYD5 decreases HIV-1 transcription in cell lines and primary CD4+ T cells. Tat expression increases SMYD5 protein levels in a manner dependent on the Tat cofactor USP11. |
ChIP assay (in vivo promoter association), RNA binding assay (TAR element), in vitro methylation assay (Tat substrate), SMYD5 knockdown in cell lines and primary T cells, HIV-1 transcription reporter assays |
Cell reports |
Medium |
36897778
|
| 2024 |
SMYD5 represses the key mild hypothermia response (MHR) gene SP1 at euthermia; this repression correlates with temperature-dependent levels of H3K36me3 at the SP1 locus and globally, identified through a forward CRISPR-Cas9 mutagenesis screen. |
Forward CRISPR-Cas9 mutagenesis screen, ChIP analysis for H3K36me3, transcriptional reporter/gene expression assays |
Cell reports |
Medium |
39083378
|
| 2016 |
Loss of Smyd5 in zebrafish (morpholino knockdown and CRISPR/Cas9 knockout) leads to increased expression of primitive and definitive hematopoietic markers (pu.1, mpx, l-plastin, cmyb), establishing a role for Smyd5 in restraining myeloid hematopoiesis during embryogenesis. |
Morpholino knockdown, CRISPR/Cas9 knockout in zebrafish embryos, in situ hybridization and RT-PCR for hematopoietic markers |
Scientific reports |
Medium |
27377701
|
| 2022 |
AlphaFold structural modeling of SMYD5 reveals an incomplete target lysine access channel lacking the evolutionarily conserved tri-aromatic arrangement, which correlates with low H3/H4 histone catalytic activity. SMYD5 contains a C-terminal poly-glutamic acid tract and a 30-residue MYND domain insertion that regulate structural stability, and a predicted N-terminal mitochondrial targeting signal containing a non-classical nuclear localization signal. |
AlphaFold structural prediction validated by comparison to known SMYD crystal structures using inter-residue distance maps; thermal stability assays |
Biomolecules |
Low |
35740908
|
| 2021 |
Protamine (a histone substitute in chromatin condensation during spermatogenesis) enhances SMYD5 thermal stability and physically interacts with SMYD5. The interaction is independent of the poly-E tract and MYND domain insertion. The C-terminal poly-glutamic acid tract and MYND domain M-insertion also regulate SMYD5 structural stability. Protamine has opposite (destabilizing) effects on the closely related SMYD2. |
Thermal stability assay (DSF), machine learning-assisted screening (Silver Bullets Bio library), co-precipitation/binding assays for protamine-SMYD5 interaction |
Biochemical and biophysical research communications |
Low |
33676231
|
| 2024 |
SMYD5 knockdown in lung cancer cell lines reduces H4K20 trimethylation at the SH2B3 locus, leading to increased SH2B3 expression and inhibition of cell migration and invasion via changes in epithelial-mesenchymal transition markers and MMP9 expression. |
SMYD5 knockdown in NCI-H1299 and H1703 cell lines, ChIP for H4K20me3, migration/invasion assays, EMT marker analysis |
Molecules and cells |
Low |
38723947
|
| 2025 |
SMYD5 mediates methylation of FoxO1 in fibroblast-like synoviocytes, which accelerates FoxO1 degradation through ubiquitination, promoting FLS proliferation. Additionally, SMYD5 promotes upregulation of hexokinase-2 (HK2), increasing lactate release and activating NF-κB signaling to intensify inflammation in FLS. |
Loss-of-function and gain-of-function experiments in FLS, co-immunoprecipitation (inferred from context), AAV-mediated KD in CIA mouse model, downstream pathway analysis |
Cellular & molecular biology letters |
Low |
40165083
|
| 2025 |
SMYD5 physically interacts with BRD4 in hepatocellular carcinoma cells; this interaction is identified as a potential therapeutic axis. Knockdown of SMYD5 inhibits cell proliferation and increases apoptosis in LIHC cell lines. |
Co-immunoprecipitation (interaction), functional knockdown assays, bioinformatics/in silico docking |
Pharmaceuticals (Basel, Switzerland) |
Low |
40872497
|