Frequent chromosomal translocations induced by DNA double-strand breaks

The faithful repair of DNA damage such as chromosomal double-strand breaks (DSBs) is crucial for genomic integrity. Aberrant repair of these lesions c an result in chromosomal rearrangements, including translocations, which ar e associated with numerous tumours(1,2). Models predict that some transloca tions arise from DSB-induced recombination in differentiating lymphoid cell types(3-5) or from aberrant repair of DNA damage induced by irradiation or other agents(6-8); however, a genetic system to study the aetiology of the se 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 rn d that two DSBs, each on different chromosomes, are sufficient to promote f requent reciprocal translocations. The results are in striking contrast wit h interchromosomal repair of a single DSB in an analogous system in which t ranslocations are not recovered. Thus, while interchromosomal DNA repair do es not result in genome instability per se, the presence of two DSBs in a s ingle cell can alter the spectrum of repair products that are recovered.