BCL2 oncogene translocation is mediated by a chi-like consensus.

Abstract

SummaryExamination of 64 translocations involving the major breakpoint region (mbr) of the BCL2 oncogene and the immunoglobulin heavy chain locus identified three short (14, 16, and 18 bp) segments within the mbr at which translocations occurred with very high frequency. Each of these dusters was associated with a 15-bp region of sequence homology, the principal one containing an octamer related to X, the procaryotic activator of recombination. The presence of short ddetions and N nucleotide additions at the breakpoints, as well as involvement of J. and D. coding regions, suggested that these sequences served as signals capable of interacting with the VDJ recombinase complex, even though no homology with the traditional heptamer/spacer/nonamer (IgRSS) existed. Furthermore, the BCL2 signal sequences were employed in a bidirectional fashion and could mediate recombination of one mbr region with another. Segments homologous to the BCL2 signal sequences flanked individual members of the XP family of diversity gene segments, which were themselves highly overrepresented in the reciprocal products (18q-) of BCL2 translocation. We propose that the x-like signal sequences of BCL2 represent a distinct class of recognition sites for the recombinase complex, responsible for initiating interactions between regions of DNA separated by great distances, and that BCL2 translocation begins by a recombination event between mbr and Dx~ X signals. Since recombinant joints containing X, not IgKSS, occur in brain cells expressing RAG-1 (Matsuoka, M., F. Nagawa, K. Okazaki, L. Kingsbury, K. Yoshida, U. Muller, D. T. Larue, J. A. Winer, and H. Sakano. 1991. Science [Wash. DC]. 254:81; reference 1), we further suggest that the product of this gene could mediate both BCL2 translocation and the first step of normal DJ assembly through the creation of X joints, rather than signal or coding joints.

t(14;18), a journey to eternity

“…17 and Meijerink, unpublished observation). In the reciprocal chromosome 18q − , a D H gene segment is coupled to the remaining bcl-2 sequences.…”

“…In the reciprocal chromosome 18q − , a D H gene segment is coupled to the remaining bcl-2 sequences. [17][18][19] Random nucleotides, denoted 'N-nucleotides', are present at both translocational junctions, and resemble random nucleotides which are present in the V H -D H and D H -J H junctions and which are randomly inserted by terminal-deoxy transferase during the IgH assembly process. It is now generally believed that the t(14;18) most likely results from a mistake during the IgH rearrangement process in the pre-B cell stage.…”

DNA structures at chromosomal translocation sites

“…2B). (3,11) The characteristic precision and frequency profile within the bcl-2 Mbr indicate some strong local regional specificity to the bcl-2 Mbr, as discussed later.…”

“…This is the most-common chromosomal translocation in human cancer, accounting for almost all follicular lymphomas. (3,(6)(7)(8)(9)(10)(11) The t(14,18)(q32;q21) translocation occurs at the bcl-2 gene of chromosome 18, activates the protooncogene bcl-2, leads to bcl-2 overexpression and aborts programmed cell death, which in turn leads to the lymphoma. (3,5,12) Although the bcl-2 gene is more than 200 kb long, T-cells or B-cells about 75% of translocations occur within a relatively small 150 bp sequence located in the untranslated portion of the third exon, designated as the major breakpoint region (Mbr) ( Fig.…”

“…2A). (3,10,11,13) Within the 150 bp, there are three peaks of breakage, each about 15 to 20 bp in size (Fig. 2B).…”