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Frequent chromosomal translocations induced by DNA double-strand breaks

Nature volume 405, pages 697–700 (2000)Cite this article

Abstract

The faithful repair of DNA damage such as chromosomal double-strand breaks (DSBs) is crucial for genomic integrity. Aberrant repair of these lesions can result in chromosomal rearrangements, including translocations, which are associated with numerous tumours1,2. Models predict that some translocations arise from DSB-induced recombination in differentiating lymphoid cell types3,4,5 or from aberrant repair of DNA damage induced by irradiation or other agents6,7,8; however, a genetic system to study the aetiology of these events has been lacking. Here we use a mouse embryonic stem cell system to examine the role of DNA damage on the formation of translocations. We find that two DSBs, each on different chromosomes, are sufficient to promote frequent reciprocal translocations. The results are in striking contrast with interchromosomal repair of a single DSB in an analogous system in which translocations are not recovered. Thus, while interchromosomal DNA repair does not result in genome instability per se, the presence of two DSBs in a single cell can alter the spectrum of repair products that are recovered.

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Figure 1: Translocation substrates.
Figure 2: Analysis of neo+ clones.
Figure 3: Visualization of translocations by FISH using whole chromosome mouse chromosome14-FITC (green) and chromosome17-Cy3 (red) probes.

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Acknowledgements

We thank Hein te Riele (Amsterdam) for materials, D. Tabarini in the core sequencing facility, and K. Manova and S. Kerns in the core microscopy facility. C.R. is a recipient of the Vrushalli Ranadive Fellowship from the Leukemia and Lymphoma Society, formerly the Leukemia Society of America. This work was supported by a grant from the National Science Foundation to M.J.

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  1. Cell Biology Program, Memorial Sloan-Kettering Cancer Centre and Cornell University Graduate School of Medical Sciences, 1275 York Avenue, New York, 10021, New York, USA

    Christine Richardson & Maria Jasin

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  2. Maria Jasin
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Correspondence to Maria Jasin.

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Richardson, C., Jasin, M. Frequent chromosomal translocations induced by DNA double-strand breaks. Nature 405, 697–700 (2000). https://doi.org/10.1038/35015097

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