Homologous Recombination-Directed Mechanisms of Alternative Lengthening of Telomeres
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Homologous recombination
Cell Biology
Molecular Biology
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https://repository.upenn.edu/cgi/viewcontent.cgi?filename=1&article=3441&context=edissertations&type=additional
https://repository.upenn.edu/cgi/viewcontent.cgi?filename=2&article=3441&context=edissertations&type=additional
https://repository.upenn.edu/cgi/viewcontent.cgi?filename=3&article=3441&context=edissertations&type=additional
https://repository.upenn.edu/cgi/viewcontent.cgi?filename=4&article=3441&context=edissertations&type=additional
https://repository.upenn.edu/cgi/viewcontent.cgi?filename=5&article=3441&context=edissertations&type=additional
https://repository.upenn.edu/cgi/viewcontent.cgi?filename=6&article=3441&context=edissertations&type=additional
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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, ∼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.
Advisor
Michael A. Lampson