Lee Zou, PhD
Cancer cells rely on telomerase or the alternative lengthening of telomeres (ALT) pathway to overcome replicative mortality. ALT is mediated by recombination and is prevalent in a subset of human cancers; however, whether or not it can be exploited therapeutically remains unknown. Loss of ATRX is associated with ALT in cancers. In this study, we showed that ATRX loss compromises the cell cycle regulation of the telomeric noncoding RNA TERRA and leads to persistent association of replication protein A (RPA) with telomeres after DNA replication, creating a recombinogenic nucleoprotein structure. Inhibition of ATR, a critical regulator of recombination recruited by RPA, disrupts ALT and triggers chromosome fragmentation and apoptosis in ALT cells. Importantly, the cell death induced by ATR inhibitors is highly selective for ALT cells across a panel of cancer cell lines, suggesting that ATR inhibition is a potential therapeutic strategy for the treatment of ALT-positive cancers.

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