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BCL2 oncogene translocation is mediated by a chi-like consensus
R T Wyatt1, R A Rudders, A Zelenetz
1Department of Medicine (Hematology/Oncology), New England Medical Center Hospitals, Boston, Massachusetts 02111.
The Journal of Experimental Medicine
|June 1, 1992
Summary
The BCL2 oncogene translocation involves specific DNA segments with homology to a bacterial recombination activator, suggesting a novel mechanism for DNA recombination in human cells. These chi-like sequences may initiate BCL2 translocations and normal gene assembly.
Area of Science:
- Molecular Biology
- Genetics
- Oncology
Background:
- Translocations involving the BCL2 oncogene and immunoglobulin heavy chain locus are implicated in certain cancers.
- The precise molecular mechanisms initiating these translocations are not fully understood.
Purpose of the Study:
- To identify specific DNA sequences and mechanisms involved in BCL2 oncogene translocations.
- To investigate the role of novel recombination signals in DNA rearrangement.
Main Methods:
- Analysis of 64 translocations involving the BCL2 major breakpoint region (mbr) and immunoglobulin heavy chain locus.
- Sequence analysis to identify homologous regions and potential recombination signals.
- Examination of breakpoint junctions for deletions, additions, and involvement of specific gene segments.
Main Results:
- Identified three short segments within the BCL2 mbr (14, 16, 18 bp) as high-frequency translocation sites.
- Discovered a 15-bp region of sequence homology, including an octamer related to the bacterial recombination activator chi.
- Observed deletions and N nucleotide additions at breakpoints, suggesting interaction with the VDJ recombinase complex.
- Found that BCL2 signal sequences flank diversity gene segments and are overrepresented in translocation products.
- Demonstrated bidirectional function of BCL2 signal sequences in mediating recombination.
Conclusions:
- The BCL2 chi-like signal sequences represent a novel class of recognition sites for the recombinase complex.
- These sequences initiate DNA interactions over long distances, leading to BCL2 translocation via recombination between mbr and DXP chi signals.
- The BCL2 gene product may mediate both BCL2 translocation and normal DJ gene assembly through chi joint formation.