A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex

Sathees C. Raghavan, Patrick Swanson, Xlantuo Wu, Chih Lin Hsieh, Michael R. Lieber

Research output: Contribution to journalArticle

184 Citations (Scopus)

Abstract

The causes of spontaneous chromosomal translocations in somatic cells of biological organisms are largely unknown, although double-strand DNA breaks are required in all proposed mechanisms1-5. The most common chromosomal abnormality in human cancer is the reciprocal translocation between chromosomes 14 and 18 (t(14;18)), which occurs in follicular lymphomas. The break at the immunoglobulin heavy-chain locus on chromosome 14 is an interruption of the normal V(D)J recombination process. But the breakage on chromosome 18, at the Bcl-2 gene, occurs within a confined 150-base-pair region (the major breakpoint region or Mbr) for reasons that have remained enigmatic. We have reproduced key features of the translocation process on an episome that propagates in human cells. The RAG complex-which is the normal enzyme for DNA cleavage at V, D or J segments-nicks the Bcl-2 Mbr in vitro and in vivo in a manner that reflects the pattern of the chromosomal translocations; however, the Mbr is not a V(D)J recombination signal. Rather the Bcl-2 Mbr assumes a non-B-form DNA structure within the chromosomes of human cells at 20-30% of alleles. Purified DNA assuming this structure contains stable regions of single-strandedness, which correspond well to the translocation regions in patients. Hence, a stable non-B-DNA structure in the human genome appears to be the basis for the fragility of the Bcl2 Mbr, and the RAG complex is able to cleave this structure.

Original languageEnglish
Pages (from-to)88-93
Number of pages6
JournalNature
Volume428
Issue number6978
DOIs
StatePublished - Mar 4 2004

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V(D)J Recombination
Chromosomes, Human, Pair 18
Chromosomes, Human, Pair 14
Genetic Translocation
DNA
Chromosome Structures
bcl-2 Genes
Immunoglobulin Heavy Chains
DNA Cleavage
Follicular Lymphoma
Double-Stranded DNA Breaks
Human Chromosomes
Human Genome
Base Pairing
Chromosome Aberrations
Plasmids
Alleles
Enzymes
Neoplasms
In Vitro Techniques

All Science Journal Classification (ASJC) codes

  • General

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A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex. / Raghavan, Sathees C.; Swanson, Patrick; Wu, Xlantuo; Hsieh, Chih Lin; Lieber, Michael R.

In: Nature, Vol. 428, No. 6978, 04.03.2004, p. 88-93.

Research output: Contribution to journalArticle

Raghavan, Sathees C. ; Swanson, Patrick ; Wu, Xlantuo ; Hsieh, Chih Lin ; Lieber, Michael R. / A non-B-DNA structure at the Bcl-2 major breakpoint region is cleaved by the RAG complex. In: Nature. 2004 ; Vol. 428, No. 6978. pp. 88-93.
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