Emily Mason-Osann

Telomeres are repetitive DNA sequences that cap the ends of all human chromosomes and function to maintain the integrity of the genome. Telomeric DNA undergoes progressive shortening with each cell division, eventually halting the cell from continuing to divide. However, the ability to divide indefinitely, called replicative immortality, is a hallmark feature of cancer cells. Approximately 10-15% of cancers maintain telomere length using the Alternative Lengthening of Telomeres (ALT) pathway. ALT promotes telomere elongation using a mechanism that resembles homologous recombination, a specific type of DNA repair. ALT is found across a variety of different cancer types, though it tends to be more prevalent in sarcomas, such as osteosarcoma. The high prevalence of ALT in osteosarcoma is of interest because osteosarcoma is a pediatric bone cancer that currently has no targeted therapies available. If the ALT pathway could be targeted, it could make a significant impact for patients with this disease. The exact proteins and mechanisms regulating the elongation of ALT telomeres are currently unclear, making it challenging to identify therapeutic targets within the ALT pathway. RAD54 is a protein with many known functions in recombination, including stimulating the formation and resolution of branched DNA structures formed as intermediates during recombination. Preliminary data generated through this project demonstrate that loss of RAD54 leads to a decrease in ALT activity, and a significant decrease in elongation events at ALT telomeres, suggesting that RAD54 is a crucial regulator of the ALT pathway. While RAD54 has previously been shown to be involved in repairing DNA breaks, the role of RAD54 at ALT telomeres has not yet been characterized. Therefore, this project aims to determine whether ALT cells rely on RAD54 to promote telomere maintenance, thus making RAD54 a possible therapeutic target for ALT positive cancers.