5-Azacytosine induces cytotoxicity via 5-methylcytosine depletion on chromatin-associated RNA in leukemia.

5-azacytidine depletes RNA 5-methylcytosine in chromatin-associated RNA of leukemia cells, and this early-time m5C loss is sufficient to induce leukemia cell death.

• Why it matters: The clinical DNA hypomethylation model for 5-azacytidine does not explain its RNA-linked cytotoxicity, leaving the key transcriptional mechanism unclear.
• What they did: The study shows that RNA m5C depletion by 5-azacytidine causes transcriptional repression, disrupting cell-cycle and DNA repair genes, and mechanistically interferes with MBD6-mediated H2AK119ub deubiquitination, SRSF2 recruitment, and p300-driven H3K27ac deposition.
• The result: Loss of the caRNA methyltransferase NSUN2 phenocopies 5-azacytidine effects, including prolonged cell cycle, defective DNA repair, and a shift in hematopoietic lineage commitment toward erythropoiesis.

AI summary of the abstract · may contain errors · not medical advice · read the paper.