|
|
|
|||||||
|
|||||||||
J. Biol. Chem., Vol. 276, Issue 31, 29126-29133, August 3, 2001
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
From the Chromosomal translocations and deletions are
among the major events that initiate neoplasia. For lymphoid
chromosomal translocations, misrecognition by the RAG
(recombination activating gene) complex of V(D)J recombination is one
contributing factor that has long been proposed. The chromosomal
translocations involving LMO2 (t(11;14)(p13;q11)), Ttg-1
(t(11;14)(p15;q11)), and Hox11 (t(10;14)(q24;q11)) are among the
clearest examples in which it appears that a D or J segment has
synapsed with an adventitious heptamer/nonamer at a gene outside of one
of the antigen receptor loci. The interstitial deletion at 1p32
involving SIL (SCL-interrupting locus)/SCL (stem cell leukemia)
is a case involving two non-V(D)J sites that have been suggested to be
V(D)J recombination mistakes. Here we have used our human
extrachromosomal substrate assay to formally test the hypothesis that
these regions are V(D)J recombination misrecognition sites and, more
importantly, to quantify their efficiency as V(D)J recombination
targets within the cell. We find that the LMO2 fragile site functions
as a 12-signal at an efficiency that is only 27-fold lower than that of
a consensus 12-signal. The Ttg-1 site functions as a 23-signal at an
efficiency 530-fold lower than that of a consensus 23-signal. Hox11
failed to undergo recombination as a 12- or 23-signal and was at least
20,000-fold less efficient than consensus signals. SIL has been
predicted to function as a 12-signal and SCL as a 23-signal. However,
we find that SIL actually functions as a 23-signal. These results
provide a formal demonstration that certain chromosomal fragile sites
can serve as RAG complex targets, and they determine whether these
sites function as 12- versus 23-signals. These results
quantify one of the three major factors that determine the frequency of
these translocations in T-cell acute lymphocytic leukemia.
Analysis of the V(D)J Recombination Efficiency at Lymphoid
Chromosomal Translocation Breakpoints*
,¶
Departments of Pathology, Biochemistry & Molecular Biology, Molecular Microbiology & Immunology, and Biological
Sciences, Norris Comprehensive Cancer Center, University of Southern
California Keck School of Medicine, Los Angeles, California
90089-9176 and the § Medicine Branch and Department of
Genetics, NCI, National Institutes of Health, Bethesda, Maryland
20889-5105
*
This research was supported by National Institutes of Health
grants (to M. R. L.).The costs of publication of this
article were defrayed in part by the
payment of page charges. The article must therefore be hereby marked
"advertisement" in
accordance with 18 U.S.C. Section
1734 solely to indicate this fact.
Copyright © 2001 by The American Society for Biochemistry and Molecular Biology, Inc.
CiteULike 
Complore 
Connotea 
Del.icio.us 
Digg 
Reddit 
Technorati What's this?
This article has been cited by other articles:
|
|
 |
|
  M. R. Lieber, S. C. Raghavan, and K. Yu Mechanistic Aspects of Lymphoid Chromosomal Translocations J Natl Cancer Inst Monographs, July 1, 2008; 2008(39): 8 - 11. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Zhang and P. C. Swanson V(D)J Recombinase Binding and Cleavage of Cryptic Recombination Signal Sequences Identified from Lymphoid Malignancies J. Biol. Chem., March 14, 2008; 283(11): 6717 - 6727. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Curry, D. Schulz, C. J. Guidos, J. S. Danska, L. Nutter, A. Nussenzweig, and M. S. Schlissel Chromosomal reinsertion of broken RSS ends during T cell development J. Exp. Med., October 1, 2007; 204(10): 2293 - 2303. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 W. A. Dik, B. Nadel, G. K. Przybylski, V. Asnafi, P. Grabarczyk, J. M. Navarro, B. Verhaaf, C. A. Schmidt, E. A. Macintyre, J. J. M. van Dongen, et al. Different chromosomal breakpoints impact the level of LMO2 expression in T-ALL Blood, July 1, 2007; 110(1): 388 - 392. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. M. Murray, J. P. O'Neill, T. Messier, J. Rivers, V. E. Walker, B. McGonagle, L. Trombley, L. G. Cowell, G. Kelsoe, F. McBlane, et al. V(D)J Recombinase-Mediated Processing of Coding Junctions at Cryptic Recombination Signal Sequences in Peripheral T Cells during Human Development J. Immunol., October 15, 2006; 177(8): 5393 - 5404. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. S. Schlissel, C. R. Kaffer, and J. D. Curry Leukemia and lymphoma: a cost of doing business for adaptive immunity. Genes & Dev., June 15, 2006; 20(12): 1539 - 1544. [Full Text] [PDF]
|
|
|
|
|
|
A. Allam and D. Kabelitz TCR trans-Rearrangements: Biological Significance in Antigen Recognition vs the Role as Lymphoma Biomarker J. Immunol., May 15, 2006; 176(10): 5707 - 5712. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. C. Raghavan, P. C. Swanson, Y. Ma, and M. R. Lieber Double-Strand Break Formation by the RAG Complex at the Bcl-2 Major Breakpoint Region and at Other Non-B DNA Structures In Vitro Mol. Cell. Biol., July 15, 2005; 25(14): 5904 - 5919. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Raghavan, P. Chastain, J. S. Lee, B. G. Hegde, S. Houston, R. Langen, C.-L. Hsieh, I. S. Haworth, and M. R. Lieber Evidence for a Triplex DNA Conformation at the bcl-2 Major Breakpoint Region of the t(14;18) Translocation J. Biol. Chem., June 17, 2005; 280(24): 22749 - 22760. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Tsuji, H. Ishii-Ohba, T. Katsube, H. Ukai, S. Aizawa, M. Doi, K. Hioki, and T. Ogiu Involvement of Illegitimate V(D)J Recombination or Microhomology-Mediated Nonhomologous End-Joining in the Formation of Intragenic Deletions of the Notch1 Gene in Mouse Thymic Lymphomas Cancer Res., December 15, 2004; 64(24): 8882 - 8890. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. C. Raghavan, S. Houston, B. G. Hegde, R. Langen, I. S. Haworth, and M. R. Lieber Stability and Strand Asymmetry in the Non-B DNA Structure at the bcl-2 Major Breakpoint Region J. Biol. Chem., October 29, 2004; 279(44): 46213 - 46225. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. S. Boehden, A. Restle, R. Marschalek, C. Stocking, and L. Wiesmuller Recombination at chromosomal sequences involved in leukaemogenic rearrangements is differentially regulated by p53 Carcinogenesis, August 1, 2004; 25(8): 1305 - 1313. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
Y. Kitagawa, K. Inoue, S. Sasaki, Y. Hayashi, Y. Matsuo, M. R. Lieber, H. Mizoguchi, J. Yokota, and T. Kohno Prevalent Involvement of Illegitimate V(D)J Recombination in Chromosome 9p21 Deletions in Lymphoid Leukemia J. Biol. Chem., November 22, 2002; 277(48): 46289 - 46297. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. L. Wiemels, B. C. Leonard, Y. Wang, M. R. Segal, S. P. Hunger, M. T. Smith, V. Crouse, X. Ma, P. A. Buffler, and S. R. Pine Site-specific translocation and evidence of postnatal origin of the t(1;19) E2A-PBX1 fusion in childhood acute lymphoblastic leukemia PNAS, November 12, 2002; 99(23): 15101 - 15106. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. Marculescu, T. Le, P. Simon, U. Jaeger, and B. Nadel V(D)J-mediated Translocations in Lymphoid Neoplasms: A Functional Assessment of Genomic Instability by Cryptic Sites J. Exp. Med., January 7, 2002; 195(1): 85 - 98. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| All ASBMB Journals | Molecular and Cellular Proteomics |
| Journal of Lipid Research | ASBMB Today |