Alternative lengthening of telomeres renders cancer cells hypersensitive to ATR inhibitors

摘要: Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and prevalent in a subset human cancers, yet whether it can be exploited therapeutically remains unknown. Loss chromatin-remodeling protein ATRX associates with cancers. Here, we show that loss compromises cell-cycle regulation telomeric noncoding RNA TERRA leads persistent association replication A (RPA) after DNA replication, creating recombinogenic nucleoprotein structure. Inhibition kinase ATR, critical regulator recruited RPA, disrupts triggers chromosome fragmentation apoptosis cells. The cell death induced ATR inhibitors highly selective for cancer ALT, suggesting such may useful treatment ALT-positive