Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS
- PMID: 38760575
- PMCID: PMC11183266
- DOI: 10.1038/s44318-024-00108-2
Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS
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.
Keywords: DNA–Protein Crosslinks; Genome Stability; Hypomethylating Agents; Nucleotide Metabolism; SUMO-targeted Ubiquitylation.
© 2024. The Author(s).
Conflict of interest statement
The authors declare no competing interests.
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References
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- 855741/EC | ERC | HORIZON EUROPE European Research Council (ERC)
- BE 5342/3-1/Deutsche Forschungsgemeinschaft (DFG)
- YIP4644/The Vallee Foundation
- ASP-II-4555793532/Mark Foundation For Cancer Research (The Mark Foundation for Cancer Research)
- 18796/CRUK_/Cancer Research UK/United Kingdom
- 393547839/Deutsche Forschungsgemeinschaft (DFG)
- DRCPGM\100005/Cancer Research UK (CRUK)
- 801750/EC | European Research Council (ERC)
- 213249687/Deutsche Forschungsgemeinschaft (DFG)
- C6/A18796/Cancer Research UK (CRUK)
- YIP4644/European Molecular Biology Organization (EMBO)
- 29580/Cancer Research UK (CRUK)
- 464588647/Deutsche Forschungsgemeinschaft (DFG)
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