Alternative lenghtening of telomeres in human cancer cells

ALT is a recombination based mechanism but little is known what induces or represses ALT and whether it is a defect in the recombination apparatus or a dysfunction of telomere binding proteins. Preliminary data of my first year project show, that in fact ALT cells have an intact recombination apparatus and therefore this recombination defect is restricted to the telomere ends. We intend to pursue our studies by investigating the influence of telomere binding factors, which might be involved in this recombination process as well as the role of telomere length in the process of ALT recombination. The second part of my project deals with establishing an in vitro model for ALT engagement. We intend to inhibit telomerase in mismatch repair deficient cells and therefore increase the selective pressure for the engagement of the ALT pathway in cells with a hyperrecombinogenic phenotype per se. Deciphering the mechanism of ALT engagement is crucial for molecular diagnosis of malignant diseases. We currently do not know if ALT is accompanied with a different malignant potential as compared to telomerase positive cells. In addition, once telomerase inhibitors enter clinical trials, the ALT pathway might be a backup strategy for tumor cells to gain resistance to therapy. Understanding the mechanisms of ALT is therefore fundamental for accurate diagnosis as well as risk adapted treatment strategies in patients with malignant diseases.