BCL2 major breakpoint region (mbr) may specify an origin of replication
- Tufts-New England Medical Center, Boston, MA (United States); and others
We have described a minisatellite consensus signal, GC[A/T]GG[A/T]GG, which resembles the prokaryotic activator of recombination, {chi}. The consensus appears frequently at the breakpoints of oncogene translocations, especially those in which the V(D)J recombinase has been implicated. We have investigated this relationship by examining the breakpoint positions and DNA sequence of many mbr translations from human follicular lymphomas. Breakpoints occur in three, evenly-spaced clusters 14-18 bp wide and 50 bp apart; the first cluster begins at the first base 3{prime} to the {chi} signal. At the end of cluster 3, translocations abruptly decline in frequency. We now report that this region is characterized by multiple binding sites for both single- and double-strand DNA binding proteins. Furthermore, the binding sites immediately flank clusters 1 and 3, thus defining the region at risk for translocation. The two single-strand binding proteins, one each for the sense and anti-sense strand of BCL2, bind the {chi} signal that marks the onset of translocation. The second binding site, which begins at the 3{prime} flank of cluster 3, extends a further 80 bp downstream and is absolutely required for the interaction of the mbr with factor(s) which can denature the target DNA in a cell-specific fashion. This process requires energy, as complex formation is inhibited by ATP{gamma}S. One of the two ssDNA binding proteins and, possibly, the helicase activity are expressed in a cell-cycle-dependent fashion. Finally, helical stability studies of the helicase binding region yield a profile comparable to those previously defined for several viral, yeast, and bacterial origins of replication. These studies indicate that BCL2 translocation may reflect (1) a requirement for removing a replication origin from the gene to promote lymphomagenesis and/or (2) the recombinogenic nature of such structures.
- OSTI ID:
- 133341
- Report Number(s):
- CONF-941009-; ISSN 0002-9297; TRN: 95:005313-0068
- Journal Information:
- American Journal of Human Genetics, Vol. 55, Issue Suppl.3; Conference: 44. annual meeting of the American Society of Human Genetics, Montreal (Canada), 18-22 Oct 1994; Other Information: PBD: Sep 1994
- Country of Publication:
- United States
- Language:
- English
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