The unlimited replicative capacity of human tumor cells relies on their ability to counteract the progressive loss of telomeric DNA that accompanies cell division. Eighty- five percent of cancers achieve this by up-regulating telomerase, the enzyme that adds telomere repeats to chromosome ends. The remaining 15% activate ALT (alternative lengthening of telomeres), a recombination-based mechanism. The observation that ALT is activated in a significant fraction of human tumors, combined with the notion that it may provide an adaptive mechanism to anti-telomerase therapies, indicate it as an important target for anti-cancer strategies. Recent studies identified the chromatin- remodeling factor ATRX as the protein most frequently lost in ALT, but how this loss impacts telomere recombination is not known. Our studies reveal a mechanism: loss of ATRX suppresses resolution of sister telomere cohesion at mitosis. The resulting persistent telomere cohesion promotes chromatid exchange between sister telomeres, while it suppresses inappropriate recombination between non-sisters. We hypothesize that persistent telomere cohesion is a critical component of the ALT cell state.
In Aim 1 we will elucidate the mechanisms by which loss of ATRX promotes ALT cell recombination and growth.
In Aim 2 we will investigate how loss of ATRX leads to activation of ALT.
In Aim 3 we will explore the hypothesis that up-regulation of the cohesin subunit SA1 in tumors promotes persistent telomere cohesion and an ALT-like mechanism of telomere maintenance. Understanding how recombination mediates telomere length maintenance in ALT cancers will provide insights into basic mechanisms of recombination as well as provide targets for anti-cancer therapies.
The unlimited replicative capacity of human tumor cells requires a telomere maintenance mechanism. Eighty-five percent of cancers achieve this by activating telomerase, while the remaining 15% activate ALT (alternative lengthening of telomeres), a recombination- based mechanism. Understanding how recombination mediates telomere length maintenance in ALT cancers will provide insights into basic mechanisms of recombination as well as provide targets for anti-cancer therapies.
|Smith, Susan (2018) Telomerase can't handle the stress. Genes Dev 32:597-599|
|Daniloski, Zharko; Smith, Susan (2017) Loss of Tumor Suppressor STAG2 Promotes Telomere Recombination and Extends the Replicative Lifespan of Normal Human Cells. Cancer Res 77:5530-5542|