Abstract IA19: Mechanisms of alternative telomere recombination

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 This presentation will describe unpublished data that defines signaling events that are responsible for homology directed telomere synthesis during ALT.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 ...
Source: Molecular Cancer Research - Category: Cancer & Oncology Authors: Tags: Replication Stress and DNA Damage Response: Oral Presentations - Invited Abstracts Source Type: research