3D genome organization shapes DNA damage susceptibility to platinum-based drugs

Platinum (Pt) drugs are widely utilized in cancer chemotherapy. Although cytotoxic and resistance mechanisms of Pt drugs have been thoroughly explored, it remains elusive what factors affect the receptiveness of DNA to drug-induced damage in nuclei. Here, we demonstrate that nuclear locations of chromatin play a key role in Pt drug-induced DNA damage susceptibility in vivo. By integrating data from damage-seq experiments with 3D genome structure information, we show that nuclear locations of chromatin relative to specific nuclear bodies and compartments explain patterns of cisplatin DNA damage susceptibility. This aligns with observations of cisplatin enrichment in biomolecular condensates at certain nuclear bodies. Finally, 3D structure mapping of DNA damage reveals characteristic differences between nuclear distributions of oxaliplatin-induced DNA damage in drug resistant versus sensitive cells. DNA damage increases in gene-poor chromatin at the nuclear periphery, while it decreases in gene-rich regions located at nuclear speckles. This suggests a strategic redistribution of Pt drug-induced damage in nuclei during chemoresistance development.