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Blood, 15 January 2006, Vol. 107, No. 2, pp. 777-780.
Prepublished online as a Blood First Edition Paper on September 29, 2005; DOI 10.1182/blood-2005-06-2437.
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Submitted June 20, 2005
Accepted August 23, 2005
A model of oncogenic rearrangements: differences between chromosomal translocation mechanisms and simple double-strand break repair
David M Weinstock, Beth Elliott, and Maria Jasin*
Department of Medicine, Memorial Sloan-Kettering Cancer Center, NY, NY, USA
Molecular Biology Program, Memorial Sloan-Kettering Cancer Center, NY, NY, USA
* Corresponding author; email: m-jasin{at}ski.mskcc.org.
Recurrent reciprocal translocations are present in many hematologic and mesenchymal malignancies. Because significant sequence homology is absent from translocation breakpoint junctions, nonhomologous end-joining (NHEJ) pathways of DNA repair are presumed to catalyze their formation. We developed translocation reporters for use in mammalian cells from which NHEJ events can be selected after precise chromosomal breakage. Translocations were efficiently recovered with these reporters using mouse cells and their breakpoint junctions recapitulated findings from oncogenic translocations. Small deletions and microhomology were present in most junctions; insertions and more complex events were also observed. Thus, our reporters model features of oncogenic rearrangements in human cancer cells. A homologous sequence at a distance from the break site affected the translocation junction without substantially altering translocation frequency. Interestingly, in a direct comparison, the spectrum of translocation breakpoint junctions differed from junctions derived from repair at a single chromosomal break, providing mechanistic insight into translocation formation.
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