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Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS.
- Source :
-
EMBO Journal . Jun2024, Vol. 43 Issue 12, p2397-2423. 27p. - Publication Year :
- 2024
-
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. Synopsis: The chemotherapeutic decitabine/5-aza-dC induces covalent DNMT1 DNA-protein crosslinks (DPCs), leading to DNMT1 degradation and DNA hypomethylation. This study finds that E3 ligase TOPORS promotes DNMT1-DPC degradation, while deaminase DCTD mediates a DNMT1-independent mode of 5-aza-dC cytotoxicity. The dCMP deaminase DCTD mediates 5-aza-dC cytotoxicity independently of DNA-protein crosslink formation, through the generation of 5-aza-dUMP. The ubiquitin and SUMO1 E3 ligase TOPORS is a novel player in global-genome DPC repair. TOPORS is recruited to SUMOylated DNMT1-DPCs through its SUMO-interaction motifs, whereupon it promotes DNMT1-DPC ubiquitylation and degradation. TOPORS acts in parallel to the E3 ubiquitin ligase RNF4 in mediating DNMT1-DPC tolerance. TOPORS acts in parallel to the ubiquitin ligase RNF4 in degradation of DNMT1-DNA crosslinks, thereby mediating cellular tolerance to these DPCs. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 02614189
- Volume :
- 43
- Issue :
- 12
- Database :
- Academic Search Index
- Journal :
- EMBO Journal
- Publication Type :
- Academic Journal
- Accession number :
- 177946156
- Full Text :
- https://doi.org/10.1038/s44318-024-00108-2