Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification

Journal of Experimental Medicine Cover - Vol. 196, No. 4, August 19, 2002

About the Cover

Pro–B cell lymphomas develop in mice deficient in both p53 and DNA repair proteins of the non-homologous end-joining pathway. These tumors are all characterized by nonreciprocal translocations juxtaposing the c-myc oncogene and the IgH intronic enhancer as well as amplification of both genes. The top panel illustrates the rearrangement of chromosome 12 (red-containing IgH locus) and chromosome 15 (green-containing c-myc locus). Coamplification of the IgH (red) and c-myc (yellow) loci occurs on the der(15) (bottom panel), although this chromosome is not capped by chromosome 15 subtelomeric sequences (green).

Abstract

Nonreciprocal translocations and gene amplifications are commonly found in human tumors. Although little is known about the mechanisms leading to such aberrations, tissue culture models predict that they can arise from DNA breakage, followed by cycles of chromatid fusion, asymmetric mitotic breakage, and replication. Mice deficient in both a nonhomologous end joining (NHEJ) DNA repair protein and the p53 tumor suppressor develop lymphomas at an early age harboring amplification of an IgH/c-myc fusion. Here we report that these chromosomal rearrangements are initiated by a recombination activating gene (RAG)-induced DNA cleavage. Subsequent DNA repair events juxtaposing IgH and c-myc are mediated by a break-induced replication pathway. Cycles of breakage-fusion-bridge result in amplification of IgH/c-myc while chromosome stabilization occurs through telomere capture. Thus, mice deficient in NHEJ provide excellent models to study the etiology of unbalanced translocations and amplification events during tumorigenesis.

Lab/Branch/Program: 
Laboratory of Genome Integrity
Citation: 

Evidence for replicative repair of DNA double-strand breaks leading to oncogenic translocation and gene amplification.  Difilippantonio MJ, Petersen S, Chen HT, Johnson R, Jasin M, Kanaar R, Ried T, and Nussenzweig A. J Exp Med. 2002 Aug
19;196(4):469-80.

Published Date: 
August, 2016