Date of Award
2015
Degree Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Graduate Group
Cell & Molecular Biology
First Advisor
Roger A. Greenberg
Second Advisor
Michael A. Lampson
Abstract
Telomere length maintenance is a requisite feature of cellular immortalization and a hallmark of human cancer. While most human cancers express telomerase activity, ∼10%-15% employ a recombination-dependent telomere maintenance pathway known as alternative lengthening of telomeres (ALT) that is characterized by multi-telomere clusters and associated promyelocytic leukemia protein bodies. However, the mechanisms that govern the lengthening process are poorly understood. Here, we show 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. Damaged telomeres initiate increased random surveillance of nuclear space before displaying rapid directional movement and association with recipient telomeres over micron-range distances. This phenomenon required Rad51 and the Hop2-Mnd1 heterodimer, which are essential for homologous chromosome synapsis during meiosis. Recruitment of Rad51 and Hop2 to damaged telomeres was dependent on ATR and Chk1 signaling. These findings implicate a specialized homology searching mechanism in ALT-dependent telomere maintenance and provide a molecular basis underlying the preference for recombination between nonsister telomeres during ALT.
Recommended Citation
Cho, Nam Woo, "Homologous Recombination-Directed Mechanisms of Alternative Lengthening of Telomeres" (2015). Publicly Accessible Penn Dissertations. 1655.
https://repository.upenn.edu/edissertations/1655