The role of the 3D genome organization on platinum drug induced DNA damage susceptibility

ABSTRACT: Platinum drugs (Pt drugs) are one of the most widely used chemotherapy drugs in cancer treatment. Although the cytotoxic and resistant mechanisms of Pt drugs have been thoroughly explored, it remains elusive what factors affect the receptiveness of DNA to Pt drug-induced damage. A large fraction of the genome shows significantly altered Pt drug-induced DNA damage susceptibility in the in vivo nuclear environment in comparison to isolated DNA, which cannot be explained only by the transcriptional status and DNA accessibility of the chromatin regions in vivo. Here, we demonstrate that, besides local chromatin structure, the global nuclear locations of genomic regions play a key role in modulating Pt drug-induced DNA damage susceptibility in vivo. By integrating data from damage-seq experiments with 3D genome structure information we show that the preferential nuclear locations of genomic regions relative to specific nuclear bodies and nuclear compartments can explain patterns of Pt drug DNA damage susceptibility. Thus, our observations are consistent with recent in vitro observations of an enrichment of Pt drugs in biomolecular condensates linked to certain nuclear bodies. Finally, when mapping observed DNA damage-seq signals onto 3D genome structures, we found that the 3D nuclear distribution of Pt-drug induced DNA damage differs in drug resistant cells in comparison to drug sensitve cells. In particular DNA damage increases in gene poor chromatin preferentially located in the lamina compartment, while DNA damage is decreased in gene rich regions preferentially located at nuclear speckles. This change may deter Pt-drug induced DNA damage from more viable gene dense chromatin regions that are crucial for short term cell survival. This observation suggests a selective spatial redistribution of Pt drug action in the nucleus during the emergence of chemoresistance. These observations are relevant for a better understanding of Pt drug action and the development of cancer resistant cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE267578 | GEO | 2025/05/14

REPOSITORIES: GEO