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J. Biol. Chem., Vol. 281, Issue 18, 12370-12380, May 5, 2006

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DNA Cleavage of a Cryptic Recombination Signal Sequence by RAG1 and RAG2

IMPLICATIONS FOR PARTIAL V_H GENE REPLACEMENT^*

Negar S. Rahman, LeAnn J. Godderz¹, Stephen J. Stray², J. Donald Capra, and Karla K. Rodgers³

From the Department of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma 73190, Molecular Immunogenetics Research Program, Oklahoma Medical Research Foundation, Oklahoma City, Oklahoma 73104

Antibody and T cell receptor genes are assembled from gene segments by V(D)J recombination to produce an almost infinitely diverse repertoire of antigen specificities. Recombination is initiated by cleavage of conserved recombination signal sequences (RSS) by RAG1 and RAG2 during lymphocyte development. Recent evidence demonstrates that recombination can occur at noncanonical RSS sites within Ig genes or at other loci, outside the context of normal lymphocyte receptor gene rearrangement. We have characterized the ability of the RAG proteins to bind and cleave a cryptic RSS (cRSS) located within an Ig V_H gene segment. The RAG proteins bound with sequence specificity to either the consensus RSS or the cRSS. The RAG proteins nick the cRSS on both the top and bottom strands, thereby bypassing the formation of the DNA hairpin intermediate observed in RAG cleavage of canonical RSS substrates. We propose that the RAG proteins may utilize an alternative mechanism for double-stranded DNA cleavage, depending on the substrate sequence. These results have implications for further diversification of the antigen receptor repertoire as well as the role of the RAG proteins in genomic instability.

Received for publication, July 20, 2005 , and in revised form, March 8, 2006.

^* This work was supported by Oklahoma Center for Advancement in Science and Technology awards for project numbers HR02-008 and HR05-101 (to K. K. R.) and National Institutes of Health Grant AI-12127 (to J. D. C.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1 and 2.

¹ Supported by a National Science Foundation Graduate Research Fellowship.

² Present address: Dept. of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73190.

³ To whom correspondence should be addressed: Dept. of Biochemistry and Molecular Biology, University of Oklahoma Health Sciences Center, 940 S. L. Young Blvd., Oklahoma City, OK 73190. Tel.: 405-271-2227 (ext. 1248); Fax: 405-271-3139; E-mail: karla-rodgers{at}ouhsc.edu.

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