Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS

Carnie, Christopher J; Götz, Maximilian J; Palma-Chaundler, Chloe S; Weickert, Pedro; Wanders, Amy; Serrano-Benitez, Almudena; Li, Hao-Yi; Gupta, Vipul; Awwad, Samah W; Blum, Christian J; Sczaniecka-Clift, Matylda; Cordes, Jacqueline; Zagnoli-Vieira, Guido; D’Alessandro, Giuseppina; Richards, Sean L; Gueorguieva, Nadia; Lam, Simon; Beli, Petra; Stingele, Julian; Jackson, Stephen P (2024): Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS. The EMBO Journal, 43 (12). pp. 2397-2423. ISSN 1460-2075

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.

• Doc-Type: Article (LMU)
• Organisational unit (Faculties): 18 Chemistry and Pharmacy > Department of Biochemistry
• DFG subject classification of scientific disciplines: Life sciences
• DFG: Funded by the Deutsche Forschungsgemeinschaft (DFG, German Research Foundation) - 491502892