Project Summary Telomere length maintenance is essential for the growth of cancer cells. My lab has been studying the function of telomeres and telomerase and their connection to cancer for over 25 years. While telomerase activity maintains telomeres in most cancer cells, a subset of cells maintain long telomeres through a recombination based mechanism and through other less well characterized pathways. The revolution in cancer genomics has offered a new approach to identify pathways that maintain telomeres in cancer and also genes that cooperate with telomerase to promote immortal growth. To identify new approaches to block cancer growth, we are taking biochemical, genetic and bioinformatic approaches to study telomeres. We will use the powerful new assay, ADDIT, that we developed to probe mechanisms and cooperation of telomere regulatory pathways. We will also mine data in The Cancer Genome Atlas to identify new mechanism of length regulation. This work will establish a detailed mechanistic understanding of telomere length regulation as well as develop biomarkers to move toward individualized therapeutics for targeting the telomere in cancer.