| Summary: | Cisplatin (CP), which is a conventional cancer chemotherapeutic drug, induces apoptosis by modulating a diverse array of gene regulatory mechanisms. However, cisplatin-mediated changes in the m<sup>6</sup>A methylome are unknown. We employed an m<sup>6</sup>A miCLIP-seq approach to investigate the effect of m<sup>6</sup>A methylation marks under cisplatin-mediated apoptotic conditions on HeLa cells. Our high-resolution approach revealed numerous m<sup>6</sup>A marks on 972 target mRNAs with an enrichment on 132 apoptotic mRNAs. We tracked the fate of differentially methylated candidate mRNAs under <i>METTL3</i> knockdown and cisplatin treatment conditions. Polysome profile analyses revealed perturbations in the translational efficiency of <i>PMAIP1</i> and <i>PHLDA1</i> transcripts. Congruently, <i>PMAIP1</i> amounts were dependent on <i>METTL3</i>. Additionally, cisplatin-mediated apoptosis was sensitized by <i>METTL3</i> knockdown. These results suggest that apoptotic pathways are modulated by m<sup>6</sup>A methylation events and that the <i>METTL3–PMAIP1</i> axis modulates cisplatin-mediated apoptosis in HeLa cells.
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