title: Interchromosomal homology searches drive directional ALT telomere movement and synapsis.
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.
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors.forename: Nam Woo
authors.initials: NW
authors.lastname: Cho
authors.affiliation: Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, 421 Curie Boulevard, Philadelphia, PA 19104-6160, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Dilley
authors.affiliation: Department of Biology, University of Pennsylvania, Philadelphia, PA 19104, USA.
authors.forename: Michael A
authors.initials: MA
authors.lastname: Lampson
authors.affiliation: 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.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Greenberg
mesh_terms: D018797:Cell Cycle Proteins / Q000378:metabolism; D045744:Cell Line, Tumor; D002843:Chromatin / Q000378:metabolism; D023902:Chromosome Pairing; D053903:DNA Breaks, Double-Stranded; D059765:Homologous Recombination; D006801:Humans; D009687:Nuclear Proteins / Q000378:metabolism; D011995:Recombination, Genetic; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific) / Q000378:metabolism; D016615:Telomere / Q000378:metabolism*; D035321:Telomeric Repeat Binding Protein 1 / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism
chemical_list: D018797:Cell Cycle Proteins; D002843:Chromatin; C510357:MND1 protein, human; D009687:Nuclear Proteins; C443678:PSMC3IP protein, human; D035321:Telomeric Repeat Binding Protein 1; D015534:Trans-Activators; C058668:DNA modification methylase FokI; D015265:Site-Specific DNA-Methyltransferase (Adenine-Specific)