Alternative lengthening of telomeres: induction, maintenance and vulnerabilities

To divide indefinitely, cancer cells must maintain their chromosome ends (called telomeres). Cancers solve this problem by either expressing an enzyme that lengthens telomeres or by recombining and copying telomeres by Alternative Lengthening of Telomeres (ALT). ALT cancers are very aggressive and there are currently no targeted treatments. Until recently, it was not possible to induce ALT in the laboratory. However, we discovered a virus, KSHV, which induces ALT as a means to copy its own DNA. We aim to exploit this finding to interrogate the mechanism of ALT induction. To discover factors essential for ALT, we have also identified proteins that are specifically enriched at ALT telomeres. We will screen these proteins to identify those that are essential for the survival of ALT cancers but are dispensable in normal cells. Our proposal will transform our understanding of the ALT mechanism and may reveal vulnerabilities that could be exploited therapeutically.