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Spatial Dynamics of Chromosome Translocations in Living Cells

Science  09 Aug 2013:
Vol. 341, Issue 6146, pp. 660-664
DOI: 10.1126/science.1237150

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Chromosome Choreography

Chromosome translocations arise through the illegitimate pairing of broken chromosome ends and are commonly found in many cancers. Roukos et al. (p. 660) used ultrahigh-throughput time-lapse imaging on human tissue culture cells containing marked chromosomes to capture very rare translocation events. Double-strand breaks in the DNA underwent an initial “partner search,” with a fraction of the ends moving into spatial proximity to each other, which resulted in persistent pairing and the merging of DNA repair foci. Most paired ends arose from breaks in close proximity, but occasionally translocations formed from more distantly positioned breaks. Proteins of the DNA repair machinery could influence the pairing and/or translocation process.

Abstract

Chromosome translocations are a hallmark of cancer cells. We have developed an experimental system to visualize the formation of translocations in living cells and apply it to characterize the spatial and dynamic properties of translocation formation. We demonstrate that translocations form within hours of the occurrence of double-strand breaks (DSBs) and that their formation is cell cycle–independent. Translocations form preferentially between prepositioned genome elements, and perturbation of key factors of the DNA repair machinery uncouples DSB pairing from translocation formation. These observations generate a spatiotemporal framework for the formation of translocations in living cells.

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