Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS
EMBO Journal article from the Stingele (A34) and Jackson labs
17.05.2024
Christopher J Carnie, Maximilian J Götz, Chloe S Palma-Chaundler, Pedro Weickert, Amy Wanders, Almudena Serrano-Benitez, Hao-Yi Li, Vipul Gupta, Samah W Awwad, Christian J Blum, Matylda Sczaniecka-Clift, Jacqueline Cordes, Guido Zagnoli-Vieira, Giuseppina D’Alessandro, Sean L Richards, Nadia Gueorguieva, Simon Lam, Petra Beli, Julian Stingele and Stephen P Jackson (2024 May 17) Decitabine cytotoxicity is promoted by dCMP deaminase DCTD and mitigated by SUMO-dependent E3 ligase TOPORS. EMBO J. https://doi.org/10.1038/s44318-024-00108-2
Abstract cited directly from the article:
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.