Induction of chromosomal translocations in mouse and human cells using site-specific endonucleases

Abstract

Reciprocal chromosomal translocations are early and essential events in the malignant transformation of several tumor types, yet the precise mechanisms that mediate translocation formation are poorly understood. We review here the development of approaches to induce and recover translocations between two targeted DNA double-strand breaks (DSBs) in mammalian chromosomes. Using mouse cells, we find that nonhomologous end-joining readily mediates translocation formation between two DSBs generated by site-specific endonucleases. Translocations occur much less frequently, however, than intrachromosomal repair of a single DSB. Translocation junctions obtained with this approach have similar end modifications to translocation junctions found in human tumors, including deletions, insertions, and repair at short stretches of homology. These modifications are more extensive than repair junctions at a single DSB, suggesting that different factors may be involved in translocation formation and repair of a single DSB. Finally, we describe a novel approach to induce translocations in human cells. Translocation model systems provide an opportunity to study the involvement of mammalian DNA repair and signaling factors in the etiology of chromosomal rearrangements. © The Author 2008. Published by Oxford University Press. All rights reserved.