| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
,
* Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110; and
Department of Pathology and Laboratory Medicine, Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, University of Pennsylvania School of Medicine and
Abramson Family Cancer Research Institute, Philadelphia, PA 19104
During lymphocyte Ag receptor gene assembly, DNA cleavage by the Rag proteins generates pairs of coding and signal ends that are normally joined into coding joints and signal joints, respectively, by the classical nonhomologous end-joining (NHEJ) pathway of DNA double strand break repair. Coding and signal ends can also be aberrantly joined to each other, generating hybrid joints, through NHEJ or through NHEJ-independent pathways, such as Rag-mediated transposition. Hybrid joints do not participate in the formation of functional Ag receptor genes and can alter the configuration of Ag receptor loci in ways that limit subsequent productive rearrangements. The formation of these nonfunctional hybrid joints occurs rarely in wild type lymphocytes, demonstrating that mechanisms exist to limit both the NHEJ-dependent and the NHEJ-independent joining of a signal end to a coding end. In contrast to wild-type cells, hybrid joint formation occurs at high levels in ataxia telangiectasia mutated (Atm)-deficient lymphocytes, suggesting that Atm functions to limit the formation of these aberrant joints. In this study, we show that hybrid joint formation in Atm-deficient cells requires the NHEJ proteins Artemis, DNA-PKcs, and Ku70, demonstrating that Atm functions primarily by modulating the NHEJ-dependent, and not the NHEJ-independent, joining of coding ends to signal ends.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was supported by the National Institutes of Health grants AI47829 and AI1074953 and American Cancer Society grant RSG-05–070-01-LIB (to B.P.S.).
2 Address correspondence and reprint requests to Dr. Barry P. Sleckman, Department of Pathology and Immunology, 660 S. Euclid Avenue, Campus Box 8118, Washington University School of Medicine, St. Louis, MO 63110. E-mail address: Sleckman{at}immunology.wustl.edu
3 Abbreviations used in this paper: DSB, double strand break, NHEJ, non-homologous end joining; RS, recombination signal; Atm, ataxia telangiectasia mutated; hCD4, human CD4.
This article has been cited by other articles:
|
|
 |
|
  D. Nowak, E. Le Toriellec, M.-H. Stern, N. Kawamata, T. Akagi, M. J. Dyer, W.-K. Hofmann, S. Ogawa, and H. P. Koeffler Molecular allelokaryotyping of T-cell prolymphocytic leukemia cells with high density single nucleotide polymorphism arrays identifies novel common genomic lesions and acquired uniparental disomy Haematologica, April 1, 2009; 94(4): 518 - 527. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. A. Helmink, A. L. Bredemeyer, B.-S. Lee, C.-Y. Huang, G. G. Sharma, L. M. Walker, J. J. Bednarski, W.-L. Lee, T. K. Pandita, C. H. Bassing, et al. MRN complex function in the repair of chromosomal Rag-mediated DNA double-strand breaks J. Exp. Med., March 16, 2009; 206(3): 669 - 679. [Abstract] [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
