Both V(D)J coding ends but neither signal end can recombine at the bcl-2 major breakpoint region, and the rejoining is ligase IV dependent.
The t(14;18) chromosomal translocation is the most common translocation in human cancer, and it occurs in all follicular lymphomas. The 150-bp bcl-2 major breakpoint region (Mbr) on chromosome 18 is a fragile site, because it adopts a non-B DNA conformation that can be cleaved by the RAG complex. The non-B DNA structure and the chromosomal translocation can be recapitulated on intracellular human minichromosomes where immunoglobulin 12- and 23-signals are positioned downstream of the bcl-2 Mbr. Here we show that either of the two coding ends in these V(D)J recombination reactions can recombine with either of the two broken ends of the bcl-2 Mbr but that neither signal end can recombine with the Mbr. Moreover, we show that the rejoining is fully dependent on DNA ligase IV, indicating that the rejoining phase relies on the nonhomologous DNA end-joining pathway. These results permit us to formulate a complete model for the order and types of cleavage and rejoining events in the t(14;18) translocation.
Raghavan
Sathees C
SC
USC Norris Comprehensive Cancer Ctr., Rm. 5428, 1441 Eastlake Ave., Los Angeles, CA 90089-9176, USA.
Hsieh
Chih-Lin
CL
Lieber
Michael R
MR
D001483:Base Sequence; D019457:Chromosome Breakage / Q000235:genetics*; D002883:Chromosomes, Human, Pair 14; D002887:Chromosomes, Human, Pair 18; D000072481:DNA Ligase ATP; D011088:DNA Ligases / Q000502:physiology*; D015321:Gene Rearrangement / Q000502:physiology*; D019254:Genes, bcl-2 / Q000502:physiology*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008969:Molecular Sequence Data; D011995:Recombination, Genetic / Q000502:physiology; D014178:Translocation, Genetic
D007135:Immunoglobulin Variable Region; C000607893:LIG4 protein, human; D011088:DNA Ligases; D000072481:DNA Ligase ATP