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.

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Additional Files

Movie S1-WT.mov (1282 kB)
Movie S2-D450A.mov (1628 kB)
Movie S3-TRF1only.mov (1072 kB)
Movie S4-GFPRad51.mov (40 kB)
Movie S5-siCTL.mov (1050 kB)
Movie S6-siRad51.mov (266 kB)
Movie S7-siHop2.mov (846 kB)

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