ArticleThe EMBO journal2024
Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS.
Article in The EMBO journal, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 23 papers.
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The trial behind it
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Who cites it
23 citing papers in PubMed.
- Clinical response to azacitidine in MDS is associated with distinct DNA methylation changes in HSPCs.Nature communications · 2025Trial
- SUMOylation enhances DNMT1 function to repress mega-intergenic RNAs and viral mimicry.Nature genetics · 2026Article
- Potentially Functional Variants ofCancers · 2026Article
- Reduced Maintenance DNA Methylation Thresholds Enable Sensitive Reporter Assays for UHRF1 and DNMT1 Inhibition.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- USP7 inhibition perturbs proteostasis and tumorigenesis in triple-negative breast cancer.NPJ breast cancer · 2026Article
- Structure-guided design of 7-azaindole DNMT1 inhibitors active against hypomethylating agent-resistant acute myeloid leukemia.Proceedings of the National Academy of Sciences of the United States of America · 2026Article
- Synthetic lethality of decitabine plus ATR inhibition for TP53-mutated AML.Blood advances · 2026Article
- RRM1 inhibition sensitizes lung adenocarcinoma to decitabine treatment.Cell death & disease · 2026Article
- p53 status determines the epigenetic response to demethylating agents azacitidine and decitabine.EMBO reports · 2026Article
- Discovery of a Novel DNMT1 Inhibitor with Improved Efficacy in Treating β-Thalassemia.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Gastrointestinal adverse reactions and metabolism-nutrition disorders associated with hypomethylating agents: a pharmacovigilance study with exploratory mechanistic analysis.Frontiers in nutrition · 2026Article
- Non-covalent SUMO interactions with ligases and effectors: SUMO-interacting motifs and beyond.Essays in biochemistry · 2025Review
- DNA double strand break repair: a model of specificity and complexity in SUMO signalling.Essays in biochemistry · 2025Review
- The cancer-testis lncRNA LINC01940 promotes gastric cancer malignant progression and chemoresistance by enhancing ribosome biogenesis via TAF15-mediated NOL11 SUMOylation.Cellular & molecular biology letters · 2025Article
- Cysteine-reactive covalent chloro-N-acetamide ligands induce ferroptosis mediated cell death.EMBO reports · 2025Article
- Induced proximity to PML protects TDP-43 from aggregation via SUMO-ubiquitin networks.Nature chemical biology · 2025Article
- Allosteric activation of the SPRTN protease by ubiquitin maintains genome stability.Nature communications · 2025Article
- CDADC1 is a vertebrate-specific dCTP deaminase that metabolizes gemcitabine and decitabine to prevent cellular toxicity.Proceedings of the National Academy of Sciences of the United States of America · 2025Article
- Plakophilin 1 in cancer: context-dependent dualism, subcellular dynamics, and therapeutic targeting.Frontiers in cell and developmental biology · 2025Review
- PARP inhibitor augments anti-tumor efficacy of DNMT inhibitor by inducing senescence in cholangiocarcinoma.International journal of biological sciences · 2025Article
Corrections and comments
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Authors and funding
20 authors.
Funding
Abstract
The nucleoside analogue decitabine (or 5-aza-dC) is used to treat several haematological cancers. Upon its triphosphorylation and incorporation into DNA, 5-aza-dC induces covalent DNA methyltransferase 1 DNA-protein crosslinks (DNMT1-DPCs), leading to DNA hypomethylation. However, 5-aza-dC's clinical outcomes vary, and relapse is common. Using genome-scale CRISPR/Cas9 screens, we map factors determining 5-aza-dC sensitivity. Unexpectedly, we find that loss of the dCMP deaminase DCTD causes 5-aza-dC resistance, suggesting that 5-aza-dUMP generation is cytotoxic. Combining results from a subsequent genetic screen in DCTD-deficient cells with the identification of the DNMT1-DPC-proximal proteome, we uncover the ubiquitin and SUMO1 E3 ligase, TOPORS, as a new DPC repair factor. TOPORS is recruited to SUMOylated DNMT1-DPCs and promotes their degradation. Our study suggests that 5-aza-dC-induced DPCs cause cytotoxicity when DPC repair is compromised, while cytotoxicity in wild-type cells arises from perturbed nucleotide metabolism, potentially laying the foundations for future identification of predictive biomarkers for decitabine treatment.
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