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Cell. 2014 Sep 25;159(1):108-121. doi: 10.1016/j.cell.2014.08.030.

Interchromosomal homology searches drive directional ALT telomere movement and synapsis.

Author information

1
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
2
Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
3
Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA; Department of Pathology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA; Abramson Family Cancer Research Institute, Basser Research Center for BRCA, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA. Electronic address: rogergr@mail.med.upenn.edu.

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 multitelomere clusters and associated promyelocytic leukemia protein bodies. 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. 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.

PMID:
25259924
PMCID:
PMC4177039
DOI:
10.1016/j.cell.2014.08.030
[Indexed for MEDLINE]
Free PMC Article

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