The Journal of Experimental Medicine
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Published 28 January 2002. doi:10.1084/jem.20011803
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© Rockefeller University Press, 0022-1007/2002/2/309/ $5.00
The Journal of Experimental Medicine, Volume 195, Number 3, February 4, 2002 309-316

Original Article

Restrictions Limiting the Generation of DNA Double Strand Breaks during Chromosomal V(D)J Recombination

Robert E. Tillman, Andrea L. Wooley, Maureen M. Hughes, Tara D. Wehrly, Wojciech Swat and Barry P. Sleckman

Washington University School of Medicine, Department of Pathology and Immunology, St. Louis, MO 63110

Address correspondence to Barry P. Sleckman, Washington University School of Medicine, Department of Pathology and Immunology, 660 S. Euclid Ave., Campus Box 8118, St. Louis, MO 63110-1093. Phone: 314-747-8235; Fax: 314-362-4096; E-mail: Sleckman{at}Immunology.WUSTL.edu

Antigen receptor loci are composed of numerous variable (V), diversity (D), and joining (J) gene segments, each flanked by recombination signal sequences (RSSs). The V(D)J recombination reaction proceeds through RSS recognition and DNA cleavage steps making it possible for multiple DNA double strand breaks (DSBs) to be introduced at a single locus. Here we use ligation-mediated PCR to analyze DNA cleavage intermediates in thymocytes from mice with targeted RSS mutations at the endogenous TCRß locus. We show that DNA cleavage does not occur at individual RSSs but rather must be coordinated between RSS pairs flanking gene segments that ultimately form coding joins. Coordination of the DNA cleavage step occurs over great distances in the chromosome and favors intra- over interchromosomal recombination. Furthermore, through several restrictions imposed on the generation of both nonpaired and paired DNA DSBs, this requirement promotes antigen receptor gene integrity and genomic stability in developing lymphocytes undergoing V(D)J recombination.

Key Words: lymphocyte • antigen receptor • RAG • DNA cleavage • DNA repair


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