Abstract IA19: Mechanisms of alternative telomere recombination

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Abstract Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, approximately 10-15% employ a recombination-dependent telomere maintenance pathway known as Alternative Lengthening of Telomeres (ALT), an incompletely understood process that is characterized by multi-telomere clusters. We have recently shown that a DNA double-strand break (DSB) response at ALT telomeres triggers long-range movement and clustering between chromosome termini, resulting in homology-directed telomere synthesis (Cho et. al. Cell 2014). Damaged telomeres initiate increased random surveillance of nuclear volumes before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, implicating a specialized homology searching mechanism that exhibits similarities to meiotic recombination in ALT dependent telomere maintenance. This presentation will describe unpublished data that defines signaling events that are responsible for homology directed telomere synthesis during ALT. Using a novel methodology to purify nascent telomeres, we have identified the basic requirements for break induced telomere synthesis, including the specific DNA polymerases and helicases involved. Data derived from this approach reveals mechanisms of homology directed DNA synthesis that substantially differ from either normal replicative DNA synthesis or from existing models of break induced replication that have been defined in yeast. These data reveal an ordered series of events necessary for ALT telomere synthesis and have implications for homology directed DNA repair at other genomic locations. This work was supported by NIH grants GM101149, CA138835, and CA17494, and funds from the Abramson Family Cancer Research Institute and Basser Research Center for BRCA Citation Format: Roger A. Greenberg. Mechanisms of alternative telomere recombination. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA19.